Highly Efficient Asymmetric Aziridination of Unsaturated Aldehydes Promoted by Chiral Hetero-organic Catalysts

Article abstract of DOI:10.1002/cctc.201500537

Optically pure hetero-organic catalysts that bear a hydroxyl moiety, a stereogenic sulfinyl group, and a chiral amine moiety, are highly efficient in the asymmetric aziridination of unsaturated aldehydes and lead to the desired chiral products in high yields (up to 93 %) with enantiomeric excess values up to 92 %. The influence of the stereogenic centers at the sulfinyl sulfur atom and in the amine moiety on the stereochemical outcome of the title reaction is discussed. An efficient combination: Enantiomerically pure hetero-organic ligands, which bear a hydroxy moiety, a stereogenic sulfinyl group, and an enantiomeric amine moiety, are highly efficient in the asymmetric aziridination of unsaturated aldehydes to lead to the desired products in high yields (up to 93 %) and with enantiomeric excess values up to 92 %. Cbz=Carboxybenzyl.

Full text of DOI:10.1002/cctc.201500537

DOI: 10.1002/cctc.201500537
Full Papers
Highly Efficient Asymmetric Aziridination of Unsaturated
Aldehydes Promoted by Chiral Hetero-organic Catalysts
[a]
[a]
[a]
[b]
´
´
Michał Rachwalski,* Zuzanna Wujkowska, Stanisław Lesniak, and Piotr Kiełbasinski*
Optically pure hetero-organic catalysts that bear a hydroxyl
moiety, a stereogenic sulfinyl group, and a chiral amine moiety,
are highly efficient in the asymmetric aziridination of unsatu-
rated aldehydes and lead to the desired chiral products in high
yields (up to 93%) with enantiomeric excess values up to 92%.
The influence of the stereogenic centers at the sulfinyl sulfur
atom and in the amine moiety on the stereochemical outcome
of the title reaction is discussed.
Introduction
The enantioselective construction of CÀC and CÀheteroatom
bonds in the synthesis of various compounds in the enantio-
merically pure state is still a challenge for modern organic
chemists because of the high importance of such isolated ste-
reoisomers in many industrial sectors such as the pharmaceuti-
cal, food, flavor, and fragrance industries.[1] The main factor
that influences the chemical yield and optical purity of the de-
sired chiral products is the use of an appropriate chiral catalyst.
For this reason, studies on the synthesis and evaluation of new
chiral systems for asymmetric catalysis are conducted exten-
sively.[2–4]
Chiral aziridines constitute a very useful group of synthetic
intermediates for the synthesis of amino acids, natural prod-
ucts, and pharmaceuticals.[5–8] The basic reaction for the con-
struction of such chiral heterocycles with a three-membered
ring is asymmetric aziridination,[9,10] which can generally be
conducted using chiral auxiliaries[11–15] or chiral catalysts.[16–20]
This kind of asymmetric transformation often constitutes one
step in the synthetic pathway of many natural and biologically
active compounds, for example, sphinganines.[21]
Scheme 1. Catalysts for the asymmetric aziridination.
and phenylethynylzinc additions to aldehydes,[23,28] in the con-
jugate addition of diethylzinc to a,b-unsaturated carbonyl
compounds (enones),[29] and in the asymmetric Simmons–
Smith cyclopropanation.[30] An easy access to both enantiomer-
ic products using diastereomeric forms of the ligand was dem-
onstrated. Although the chirality of the amine substituent
exerts a decisive effect on the stereochemical course of all the
reactions, it was also found that the simultaneous contribution
of each functional group was responsible for the high yields
and enantiomeric excess (ee) of the products.[30,31] To continue
our interest in the field of asymmetric transformations and in
the synthesis of small heterocyclic systems[30] and, moreover, to
take all the above results into account, we have decided to
extend the scope of the applicability of our hetero-organic li-
gands[22,23] by investigating their catalytic activity in the asym-
metric aziridination of unsaturated aldehydes.
Previously, we have reported a synthesis of chiral tridentate
ligands, which contain hydroxy, sulfinyl, and amine moieties,
with two stereogenic centers at the sulfinyl sulfur atom and on
the carbon atom in the amine function (Scheme 1).[22,23] Li-
gands that bear open-chain amine functionalities are very ef-
fective catalysts for the enantioselective Henry[24] and aza-
Henry[25] reactions, direct aldol condensation,[26] and Mannich
reaction,[27] whereas their analogs that contain an aziridine ring
as the amine moiety exhibited high catalytic activity in diethyl-
´
[a] Dr. M. Rachwalski, Z. Wujkowska, Prof. S. Lesniak
Department of Organic and Applied Chemistry
´
University of Łódz
Tamka 12, 91-403 Łódz´ (Poland)
E-mail: mrach14@wp.pl
Results and Discussion
´
[b] Prof. P. Kiełbasinski
Catalyst screening
Centre of Molecular and Macromolecular Studies
Polish Academy of Sciences, Department of Heteroorganic Chemistry
Five chiral tridentate ligands prepared as described previous-
ly[21,22] were applied as catalysts to the title reaction
´
Sienkiewicza 112, 90-363 Łódz (Poland)
E-mail: piokiel@cbmm.lodz.pl
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(Scheme 1). Ligands 1c and 1d, which originated from both
enantiomers c and d of 1-(1’-naphthyl)ethylamine, were used
to study the possible match–mismatch effect of the two ste-
reogenic centers, which are located at the sulfinyl sulfur atom
and on the carbon atom in the amine function. Ligand 1a,
which bears an aziridine moiety, was selected according to the
best results in terms of chemical yield and ee obtained for the
previous asymmetric reactions catalyzed by aziridine-contain-
ing ligands.[22,27–29] Following the procedure described previ-
ously,[19] we chose the asymmetric aziridination of (E)-2-hexenal
to screen our catalysts. The reactions were performed for 4 h
(after optimization) in chloroform, using benzyl N-tosyloxycar-
bamate or N-acetoxycarbamate as “nitrene equivalents” in the
presence of 20 mol% of ligand 1 and three equivalents of
sodium acetate as a base (Scheme 2). All the reactions were
performed at room temperature. Interestingly, in all cases trans
products were obtained as the major diastereomers, which in-
dicates that the configuration of the starting alkene is retained
in the product. The results are collected in Table 1.
easily available diastereomeric catalysts with opposite enantio-
meric amine moieties.
Asymmetric aziridination of various unsaturated aldehydes
in the presence of catalyst 1d
As the best results were achieved with catalyst 1d, we decided
to study the scope of the title reaction for a series of unsatu-
rated (E)-aldehydes[19] in the presence of catalyst 1d under the
same conditions as used previously (Scheme 3). The results are
collected in Table 2.
Scheme 3. Asymmetric aziridination of unsaturated aldehydes in the pres-
ence of catalyst 1d. OTs =OTosyl.
Table 2. Asymmetric aziridination of unsaturated aldehydes in the pres-
ence of catalyst 1d.
[a]
Entry R (number)
Yield [%] [a]D
ee [%][b] dr
Absolute
configuration[c]
Scheme 2. Asymmetric aziridination of (E)-2-hexenal. Cbz=Carboxybenzyl.
Table 1. Screening of catalyst 1a–e.
1
2
3
4
5
6
n-Pr (2)
H (3)
Me (4)
Ph (5)
4-NO2-C6H4 (6) 60
4-Cl-C6H4 (7) 37
93
70
61
50
+10.8 91
+5.3 87
+20.0 88
+0.5 92[d]
+5.6 90[d]
+47.1 92[d]
15:1 2R,3S
–
R
10:1 2R,3S
15:1 2R,3S
15:1 2R,3S
15:1 2S,3R
Entry Catalyst LG
Product 2
ee dr
[%][b]
[a]
[a] In chloroform (c=1) at RT. [b] Determined using chiral HPLC for the
major diastereoisomer. [c] According to Ref. [19]. [d] Determined using
chiral HPLC after reduction to the corresponding alcohol.
Yield [a]D
[%]
Absolute
configuration[c]
1
2
3
4
5
6
1a
1b
1c
1d
1e
1d
OTs
OTs
OTs
OTs
OTs
20
62
89
93
67
À1.7 15
À7.7 65
À10.3 87
+10.8 91
À8.5 72
+10.2 86
2:1 2S,3R
5:1 2S,3R
15:1 2S,3R
15:1 2R,3S
5:1 2S,3R
15:1 2R,3S
The results summarized in Table 2 show clearly that 1d is an
effective catalyst for the asymmetric aziridination of selected
unsaturated aldehydes to lead to the desired chiral aziridine
derivatives in good chemical yields and with high ee values.
The yields for the reactions of cinnamaldehyde and p-chloro-
cinnamaldehyde (Table 1, entries 4 and 6) were moderate,
which is in agreement with reported data.[19] However, in con-
trast to the literature data, no side products were observed.
The crude reaction mixture contained only the main product
and the unreacted substrates.
OAc 90
[a] In chloroform (c=1) at RT. [b] Determined using chiral HPLC for the
major diastereoisomer. [c] According to Ref. [19].
An inspection of the results given in Table 1 reveals some in-
teresting findings. First, the title reaction, tested in the pres-
ence of catalyst 1a, which bears an aziridine moiety, proceed-
ed insignificantly in terms of yield and ee (20 and 15%, respec-
tively). Second, the application of both diastereomeric cata-
lysts 1c and 1d, which contain opposite enantiomers of 1-(1’-
naphthyl)ethylamine, led to the formation of chiral products 2
with opposite absolute configurations. This means that the ste-
reogenic centers located in the amino moieties exerted a deci-
sive influence on the absolute configuration of the products.
The small differences in their optical rotation and ee values
may be explained in terms of “match” and “mismatch” interac-
tions with the sulfinyl stereogenic center. Thus, the characteris-
tic feature of our catalysts was confirmed also in this case and
allowed both stereoisomers of product 2 to be prepared using
Although the detailed mechanism of the title reaction
cannot be presented at this stage, it seems reasonable to
assume, according to suggestions in the literature,[19] that an
initial reversible formation of the iminium intermediate 8 be-
tween enals and the amino group of the catalyst takes place.
A chiral environment in this intermediate makes the subse-
quent aza-conjugated attack of a “nitrene equivalent” proceed
stereoselectively to form a chiral enamine intermediate 9. Next,
this intermediate undergoes an intramolecular ring closure
with the release of a leaving group (LG), which is assumed to
be responsible for the general stereochemistry of the aziridina-
tion. The final iminium intermediate 10 undergoes hydrolysis
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General protocol for the asymmetric aziridination of unsatu-
rated aldehydes using chiral ligands[19]
In a round-bottomed flask, chiral catalyst 1 and benzyl N-tosyloxy-
carbamate (or N-acetoxycarbamate) (1.2 mmol) were dissolved in
chloroform (4.0 mL). To the aforementioned stirred solution, an un-
saturated aldehyde (1.0 mmol) and sodium acetate were subse-
quently added, and the reaction mixture was stirred for 5 h at RT.
After completion (TLC test), the solvent was evaporated, and the
residue was subjected to column chromatography using silica gel
and hexane with ethyl acetate in gradient as an eluent. Chemical
yields, ee (determined by chiral HPLC), optical rotation values, and
dr are collected in Tables 1 and 2.
(2R,3S)-Benzyl
2-formyl-3-propylaziridine-1-carboxylate
(2;
Table 2, entry 1): Colorless oil; 1H NMR (CDCl3): d=0.93 (t, J=
7.2 Hz, 3H), 1.43–1.65 (m, 4H), 2.77–2.85 (m, 1H), 2.97–3.03 (m,
1H), 5.14 (t, J=12.8 Hz, 1H), 5.20 (d, J=12.8 Hz, 1H), 7.32–7.37 (m,
5H), 9.15 ppm (d, J=5.0 Hz, 1H); 13C NMR (CDCl3): d=13.5, 20.2,
33.3, 44.5, 47.1, 68.5, 128.6, 128.7, 128.8, 128.9, 136.0, 160.3,
195.7 ppm. The ee was determined as described previously[19]
(ODH-column, n-hexane/iPrOH 95:5, l=210 nm, 1.0 mLminÀ1), tr
(major enantiomer)=12.1 min, tr (minor enantiomer)=13.5 min.
Other spectroscopic data for 2 are in agreement with that in
Ref. [19].
Scheme 4. Possible mechanism of catalytic asymmetric aziridination of unsa-
turated aldehydes.
to afford the desired aziridines (Scheme 4, which shows the re-
action in the presence of catalyst 1d). The unsuccessful appli-
cation of the aziridine-containing catalyst 1a (Table 1, entry 1)
speaks in favor of this mechanism as the formation of the ini-
tial iminium intermediate is impossible for a tertiary amine, the
functional group present in this catalyst.
(R)-Benzyl 2-formylaziridine-1-carboxylate (3; Table 2, entry 2):
Colorless oil; 1H NMR (CDCl3): d=2.54 (d, J=3.0 Hz, 1H), 2.65 (d,
J=5.2 Hz, 1H), 3.10–3.17 (m, 1H), 5.10–5.20 (m, 2H), 7.31–7.35 (m,
5H), 9.06 ppm (d, J=5.2 Hz, 1H); 13C NMR (CDCl3): d=30.0, 41.2,
69.3, 128.6, 128.7, 128.8, 135.5, 160.8, 196.2 ppm. The ee was deter-
mined as described previously[19] (OJ-column, n-hexane/iPrOH
90:10, l=210 nm, 1.0 mLminÀ1), tr (major enantiomer)=32.1 min,
tr (minor enantiomer)=42.0 min. Other spectroscopic data for 3
are in agreement that in with Ref. [19].
Conclusions
Chiral hetero-organic tridentate ligands that bear two stereo-
genic centers were found to be efficient catalysts for the asym-
metric aziridination of unsaturated aldehydes. The stereogenic
centers located in the amino moieties exerted a decisive influ-
ence on the stereochemical outcome of the reactions. More-
over, it should be stressed that each enantiomer of the desired
product may be achieved by the application of the respective
diastereomeric ligands.
(2R,3S)-Benzyl
2-formyl-3-methylaziridine-1-carboxylate
(4;
Table 2, entry 3): Colorless oil; 1H NMR (CDCl3): d=1.35 (d, J=
5.6 Hz, 3H), 2.85–2.94 (m, 1H), 2.95 (dd, J=4.8, 1.8 Hz, 1H), 5.15 (q,
J=12.0 Hz, 2H), 7.32–7.37 (m, 5H), 9.10 ppm (d, J=4.8 Hz, 1H);
13C NMR (CDCl3): d=16.5, 40.0, 48.2, 69.1, 128.8, 128.9, 130.0, 135.9,
160.3, 196.2 ppm. The ee was determined as described previous-
ly[19] (ODH-column, n-hexane/iPrOH 92:8, l=254 nm, 0.5 mLminÀ1),
tr (major enantiomer)=23.1 min, tr (minor enantiomer)=25.7 min.
Other spectroscopic data for 4 are in agreement with that in
Ref. [19].
Experimental Section
General
(2R,3S)-Benzyl 2-(hydroxymethyl)-3-phenylaziridine-1-carboxyl-
ate (5; after reduction; Table 2, entry 4): Colorless oil; 1H NMR
(CDCl3): d=3.65 (dd, J=2.8, 2.4 Hz, 2H), 4.12 (d, J=5.2 Hz, 1H),
4.40 (d, J=7.2 Hz, 1H), 5.15 (s, 2H), 7.25–7.38 ppm (m, 10H);
13C NMR (CDCl3): d=42.0, 47.9, 61.5, 68.9, 126.9, 128.4, 128.6, 128.7,
128.8, 128.9, 136.2, 163.0 ppm. The ee was determined as de-
scribed previously[19] (ODH-column, n-hexane/iPrOH 90:10, l=
220 nm, 1.0 mLminÀ1), tr (major enantiomer)=21.6 min, tr (minor
enantiomer)=15.8 min. Other spectroscopic data for 5 are in
agreement with that in Ref. [19].
Unless otherwise specified, all reagents were purchased from com-
mercial suppliers and used without further purification. Chloroform
was distilled from phosphorus pentoxide. H NMR spectra were re-
1
corded by using a Bruker instrument at 600 MHz with CDCl3 as sol-
vent and relative to tetramethylsilane (TMS) as the internal stan-
dard. Data are reported as s=singlet, d=doublet, t=triplet, q=
quartet, m=multiplet, b=broad. Optical rotations were measured
by using a PerkinElmer 241 MC polarimeter with a sodium lamp at
RT (c=1). Column chromatography was performed on Merck 60
silica gel. TLC was performed on Merck 60 F254 silica gel plates, and
visualization was accomplished with UV light (254 nm). The diaste-
(2R,3S)-Benzyl 2-formyl-3-(4-nitrophenyl)aziridine-1-carboxylate
1
(6; Table 2, entry 5): Yellowish oil; H NMR (CDCl3): d=3.35 (t, J=
1
reomer ratios (dr) were determined based on the H NMR spectra
2.6 Hz, 1H), 3.95 (d, J=2.6 Hz, 1H), 5.18 (q, J=12.0 Hz, 2H), 7.30–
7.37 (m, 5H), 7.42–7.49 (m, 2H), 8.16–8.20 (m, 2H), 9.48 ppm (d, J=
2.8 Hz, 1H); 13C NMR (CDCl3): d=45.5, 50.2, 69.8, 124.8, 128.1,
128.9, 129.1, 129.3, 135.7, 142.0, 148.5, 160.1, 193.7 ppm. The ee
was determined as described previously[19] (ODH-column, n-
hexane/iPrOH 94:6, l=210 nm, 0.5 mLminÀ1), tr (major enantio-
of the crude reaction mixtures. The ee values were determined by
chiral HPLC (Knauer, Chiralcel ODH). Chiral tridentate ligands 1a–
e were synthesized using procedures described previously.[21,22]
Benzyl N-tosyloxycarbamate and benzyl N-acetoxycarbamate were
synthesized according to the literature methods.[32]
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(2S,3R)-Benzyl 2-(4-chlorophenyl)-3-(hydroxymethyl)aziridine-1-
carboxylate (7; Table 2, entry 6): Yellow oil; 1H NMR (CDCl3): d=
2.30 (s, 3H), 2.71–2.76 (m, 1H), 3.48 (d, J=3.2 Hz, 1H), 3.61–3.70
(m, 1H), 4.14–4.20 (m, 1H), 5.11–5.17 (m, 2H), 7.08–7.36 ppm (m,
9H); 13C NMR (CDCl3): d=41.2, 47.9, 61.0, 68.8, 128.1, 128.7, 128.8,
128.9, 130.2, 134.2, 134.9, 136.1, 162.4 ppm. The ee was determined
as described previously[19] (OJ-column, n-hexane/iPrOH 90:10, l=
238 nm, 1.0 mLminÀ1), tr (major enantiomer)=35.5 min, tr (minor
enantiomer)=25.5 min. Other spectroscopic data for 7 are in
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Keywords: asymmetric catalysis · aldehydes · CÀC coupling ·
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