Catalytic asymmetric aziridination of α,β-unsaturated aldehydes

Article abstract of DOI:10.1002/chem.201100042

The development, scope, and application of the highly enantioselective organocatalytic aziridination of α,β-unsaturated aldehydes is presented. The aminocatalytic azirdination of α,β-unsaturated aldehydes enables the asymmetric formation of β-formyl aziri

Full text of DOI:10.1002/chem.201100042

DOI: 10.1002/chem.201100042
Catalytic Asymmetric Aziridination of a,b-Unsaturated Aldehydes
Luca Deiana,[a, c] Pawel Dziedzic,[a, c] Gui-Ling Zhao,[a, c] Jan Vesely,[a] Ismail Ibrahem,[a]
Ramon Rios,[a] Junliang Sun,[c, d] and Armando Cꢀrdova*[a, b, c]
Abstract: The development, scope, and
application of the highly enantioselec-
tive organocatalytic aziridination of
a,b-unsaturated aldehydes is presented.
The aminocatalytic azirdination of a,b-
unsaturated aldehydes enables the
asymmetric formation of b-formyl azir-
idines with up to >19:1 d.r. and
99% ee. The aminocatalytic aziridina-
tion of a-monosubstituted enals gives
access to terminal a-substituted-a-
formyl aziridines in high yields and up
to 99% ee. In the case of the organoca-
talytic aziridination of disubstituted
a,b-unsaturated aldehydes, the trans-
formations were highly diastereo- and
enantioselective and give nearly enan-
tiomerically pure b-formyl-functional-
ized aziridine products (99% ee). A
highly enantioselective one-pot cascade
sequence based on the combination of
asymmetric amine and N-heterocyclic
carbene catalysis (AHCC) is also dis-
closed. This one-pot three-component
co-catalytic transformation between
a,b-unsaturated aldehydes, hydroxyla-
mine derivatives, and alcohols gives the
corresponding
N-tert-butoxycarbonyl
and N-carbobenzyloxy-protected b-
amino acid esters with ee values rang-
ing from 92–99%. The mechanisms
and stereochemistry of all these cata-
lytic transformations are also discussed.
Keywords: asymmetric
catalysis-
aziridines domino reactions
·
·
hydroxylamines
aldehydes
·
unsaturated
Introduction
cally active azirdines are also present in nature (e.g., natural
products, such as azirdine carboxylic acid, mitomycin, porfir-
omycin, and mitiromycin) and exhibit important biologically
activities.[2] Thus, an intense research effort has been made
for the development of asymmetric methods for the enantio-
selective synthesis of aziridines. The first asymmetric proto-
cols for the synthesis of chiral aziridines were based on the
use of chiral substrates or chiral auxiliaries.[3] The research
of finding catalytic asymmetric methods by using organome-
tallic catalysts (e.g., Cu,[4] Rh,[5] Ru,[6] Mn,[7] or Ag[8]) for the
enantioselective synthesis of aziridines began in the early
1990s.[1c,9] In this context, Evans and co-workers reported
the first catalytic asymmetric aziridination of olefins with
[N-(p-toluenesulfonyl)imino]phenyliodinane by using a [bi-
s(oxazoline]Cu complex as the catalyst.[4a–c] Jacobsen and co-
workers developed the Cu-catalyzed enantioselective aziridi-
nation of cis olefins and imines.[4f] Wulff and co-workers dis-
closed an elegant catalytic enantioselective aziridination re-
action by starting from imines and diazoacetates catalyzed
by chiral borate complexes (VAPOL with borane–THF
complexes or aryl borate–VAPOL).[10] In pioneering work,
Aggarwal and co-workers developed the Rh-catalyzed asym-
metric generation of aziridines from sulfur ylides and imines
by diazo decomposition.[11] Recently, chiral Brønsted acids,
such as dicarboxylic acids[12] and phosphoric acid deriva-
tives,[13] were employed as catalysts for the aza-Darzen reac-
tions between imines and diazoacetamides to give optically
active aziridines. Quaternery ammonium salts[14] have also
been introduced as catalysts for the aziridination of cycloal-
kenones and electron-deficient olefins. The catalytic asym-
metric formation of terminal aziridines represent a challeng-
ing and attractive target, since these compounds readily un-
Since Gabrielꢀs first report on the synthesis of the smallest
N-hetrocycle in 1888,[1a] azirdines have been the target of
synthetic chemists.[1] The intrinsic ring-strain of these three-
membered cyclic compounds makes them versatile chiral
building blocks in organic synthesis. For example, aziridines
are useful starting materials for nucleophilic ring-opening
and -expansion reactions as well as 1,3-dipolar cycloaddi-
tions.[1d–l] They can also serve as useful chiral ligands, chiral
catalysts, and auxiliaries for asymmetric synthesis.[1d–h] Opti-
[a] L. Deiana, Dr. P. Dziedzic, Dr. G.-L. Zhao, Dr. J. Vesely,
Dr. I. Ibrahem, Dr. R. Rios, Prof. A. Cꢁrdova
Department of Organic Chemistry
Arrhenius Laboratory, Stockholm University
10691 Stockholm (Sweden)
Fax : (+46)8154908
E-mail: acordova@organ.su.se
armando.cordova@miun.se
[b] Prof. A. Cꢁrdova
Department of Natural Science
Engineering and Mathematics, Mid Sweden University
85170 Sundsvall (Sweden)
[c] L. Deiana, Dr. P. Dziedzic, Dr. G.-L. Zhao, Prof. J. Sun,
Prof. A. Cꢁrdova
Berzelii Center EXSELENT on Porous Materials
Arrhenius Laboratory, Stockholm University
10691 Stockholm (Sweden)
[d] Prof. J. Sun
Department of Structural Chemistry
Arrhenius Laboratory, Stockholm University
10691 Stockholm (Sweden)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100042.
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Chem. Eur. J. 2011, 17, 7904 – 7917

FULL PAPER
dergo regioselective ring-opening with various nucleophi-
les.[1b] In addition, there is no general catalytic enantioselec-
tive method for the synthesis of highly enantioenriched 2-
alkyl-substituted terminal aziridines.[15–16] Katsuki and co-
workers reported the catalytic enantioselective aziridination
of terminal alkenes catalyzed by new Ru–(Salen)(CO) com-
plexes.[17] However, they are not yet applicable to the cata-
lytic enantioselective aziridination of a,a-disubstituted al-
kenes, which are important precursors for the synthesis of
quaternary a-amino acid derivatives.[18]
With this information in our hands, we were able to pre-
dict a “retrocatalytic” analysis for a possible novel chiral
amine-catalyzed route to enantioenriched b-formyl aziri-
dines (Scheme 1). Thus, by selecting suitable substituents on
Based on our research interest in asymmetric catalysis
and green chemistry,[19] we have explored aminocatalytic
one-pot asymmetric tandem and multicomponent transfor-
mations[20–21] between hydroxylamines and a,b-unsaturated
aldehydes.[22–24] We found that the transformations exhibit
completely different chemoselectivity depending on the sub-
stituent at the N atom of the hydroxyl amine derivative,
which affects its pKa [Eqs. (1–4)].[22–24a] For example, com-
pounds containing an electron-withdrawing substituent (e.g.,
carbamate or acyl group) at the N atom leads to a tandem
aza-Michael/hemiacetal sequence to furnish 5-hydroxyoxa-
zolidine derivatives [Eq. (1)].[22] In contrast, employing an
N-aryl- or N-alkyl-substituted hydroxylamine as the sub-
strate leads to enantioselective intra- or intermolecular 1,3-
dipolar cycloadditions [Eqs. (2–3)].[23] The one-pot three-
component reaction between hydroxylamine, benzaldehyde,
and aliphatic enals leads to an asymmetric oxy-Michael re-
action [Eq. (4)].[23a] It is noteworthy, that having a protective
group on the O atom (e.g., trimethylsilyl (TMS), tert-butyl-
dimethylsilyl (TBS), Me, or Bn) of an N-carbamate-protect-
ed hydroxylamine leads to aza-conjugate addition if the enal
is aliphatic [Eq. (5)].[24] However, reacting an O-protected
N-aryl- or -alkyl-substituted hydroxylamine with an enal
leads to iminium formation.
Scheme 1. Planned enantioselective synthesis of b-formyl aziridines.
the hydroxyl amine (e.g., carbamate groups at the N atom
and acyl or tosyl groups at the O atom) a domino sequence
should be possible involving: 1) Initial aminocatalytic enan-
tioselective aza-conjugate addition of the hydroxylamine de-
rivative to an enal. 2) Subsequent irreversible amine-cata-
lyzed stereoselective intramolecular nucleophilic substitu-
tion at the now electrophilic N atom of the in situ generated
trisubstituted hydroxyl amine. 3) Leaving-group expulsion
and aziridine product formation.
In 2006, we disclosed the first chiral amine-catalyzed
asymmetric aziridination of simple linear enals based on the
vide supra explained retrocatalytic analysis.[25] This has led
to the development of aminocatalytic aziridinations of a,b-
unsaturated aldehydes and ketones.[26–27] Herein, we report
the development, the substrate scope, and one-pot applica-
tions of the amine-catalyzed enantioselective aziridination
of a,b-unsaturated aldehydes. This catalytic reaction allows
for the stereoselective aziridination of linear, a-monosubsti-
tuted, and disubstituted a,b-unsaturated aldehydes and the
corresponding b-formyl aldehyde products were formed
with high d.r. and ee values. A highly enantioselective one-
pot three-component reaction based on the combination of
asymmetric amine and N-heterocyclic carbene catalysis
(AHCC) is also disclosed. This cascade catalysis sequence
enabled the asymmetric synthesis of b-amino acid esters
(92–99% ee) by starting from linear enals, hydroxylamine
derivatives, and alcohols. The mechanism and the stereo-
chemistry of the reactions are also discussed.
Results and Discussion
Catalyst screen: After extensive screening of different suita-
ble nitrogen atom sources for the asymmetric aziridination
of trans-2-hexenal (1a), we found that acylated hydroxycar-
bamates 2 had the right properties to give the aziridination
product 3a.[28] We, therefore, began screening the reaction
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A. Cꢁrdova et al.
between 1a (0.25 mmol) and benzyl N-acetoxycarbamate 2a
(0.3 mmol) in the presence of chiral amine catalysts 5–12.
We found that proline 5 and imidazolidinone 7 did not give
any products under our reaction conditions (Table 1, en-
(Cbz)-protected hydroxylamines 2 employing 10 as the orga-
nocatalyst. Representative examples are shown in Table 2.
We found that the aziridination of 1a with benzyl acetoxy-
carbamate 2a provided the product 3a in full conversion
with 5:1 d.r. and 96% ee after 0.5 h at 408C (Table 2,
entry 2). It is noteworthy that when changing 2a to benzyl
N-tosyloxycarbamate 2b as the “nitrene equivalent” the re-
action became highly diastereoselective both at room tem-
perature and at 408C, whereas the conversion decreased
(entries 3–4). The addition of base was subsequently investi-
gated. We found that when the more base-stable benzyl N-
tosyloxycarbamate 2b was used as the nitrogen nucleophile
together with NaOAc as the addititive the reaction formed
product 3a in full conversion with excellent diastereo- and
enantioselectivity under the same reaction conditions
(entry 6). The catalytic aziridination of 1a with benzyl N-
methylsulfonyloxy carbamate 2c as the “nitrene equivalent”
was also highly enantioselective (20:1 d.r., 95% ee); howev-
er, the conversion was lower relative to the transformation
with 2b (entry 7). Based on these results, the aziridination
reaction was further investigated employing benzyl N-tosy-
loxycarbamate 2b as the nitrogen source. We found that
high stereoselectivety was achieved in toluene and CH2Cl2
(entries 8–9). The screening of different base additives (en-
tries 10–12) revealed that the employment of inorganic
bases, such as Na2CO3 and K2CO3, was also possible (en-
tries 11–12). Different catalyst loading was also employed
(entries 15–17). The reaction rate decreased at lower cata-
lyst loading without significantly affecting the stereoselectiv-
ity. It is noteworthy that product 2a could be isolated in
moderate yield with 10:1 d.r. and 97% ee when only 2.5
mol% of catalyst 10 was employed (entry 17). In fact, the
reaction could not be run more than 16–17 h since it stopped
due to hydrolysis of Cbz-NHOTs (2b) by the base additive
NaOAc (entries 16–17). The reaction between trans-2-hexe-
nal (1a) and tert-butoxycarbonyl (Boc)-NHOTs (2e) was
also investigated with different catalyst loading. The trans-
formations gave the corresponding product 3b in good con-
version with excellent d.r. and ee (entries 18–20).[30] We also
investigated the reaction between acetylated 9-fluorenylme-
thoxycarbonyl (Fmoc)-protected hydroxylamine and 2-hexe-
nal (1a), which gave the corresponding Fmoc-protected 2-
formylaziridine 3j in 63% yield with 5:1 d.r. but only
46% ee.
Table 1. Catalyst screen for the aziridination between 1a and 2a.[a]
Entry
Catalyst
Solvent
t [h]
Conv. [%][b]
d.r.[c]
ee [%][d]
1
2
3
4
5
6
7
5
6
7
8
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
24
16
24
4
4
3
4
24
0.5
0
<5
0
15
45
86
76
20
100
–
n.d.
–
1:1
1:1
9:1
5:1
>19:1
5:1
–
n.d.
–
n.d.
57
99
90
98
96
9
10
11
12
10
8
9[e]
[a] Experimental conditions: A mixture of 2a (0.30 mmol), aldehyde 1a
(0.25 mmol), and catalyst (20 mol%) in 1.0 mL solvent was stirred for
the time shown in the table. [b] Conversion into product 3a as deter-
mined by 1H NMR spectroscopic analysis. [c] Determined by 1H NMR
spectroscopic analysis. [d] Determined by chiral-phase HPLC analysis
after reduction to the corresponding alcohol 3’. [e] The reaction was per-
formed at 408C. n.d.=not determined.
tries 1 and 3). However, chiral pyrrolidine 6 formed trace
amounts of product 3a (entry 2). It was encouraging to find
that chiral pyrrolidines 8 and 9 produced more products in
4 h but with no diastereoselectivity (Table 1, entries 4–5). To
our delight, the TMS-protected dipenylprolinol 10[29] cata-
lyzed the enantioselective formation of 2-formyl-aziridine
3a in 86% conversion after 3 h with 9:1 d.r. and 99% ee
(entry 6). The TMS-protected dinaphthylprolinol 11 did also
catalyze the asymmetric azirdination of 1a with high enan-
tioselectivity (entry 7). Jørgensenꢀs diarylprolinol 12 bearing
two more bulky and electron-withdrawing 3,5-(CF3)2C6H3
moieties catalyzed the azirdination of 1a with excellent dia-
stereoselectivity and high enantioselectivity (>19:1 d.r.,
98% ee), but the conversion was only 20% after 24 h
(entry 8). It is important to note that when increasing the
temperature to 408C the reaction rate also increased with-
out significantly decreasing the stereoselectivity (entry 9).
Based on these results, we decided to select the TMS-pro-
tected dipenylprolinol 10 as the catalyst for the enantiose-
lective azirdination of enals.
Substrate scope: The release of acetate is more atom-eco-
nomic and environmentally friendly relative to the release
of tosylate. We therefore decided to investigate the aziridi-
nation reaction of linear enals 1 with both N-acetoxycarba-
mates (2a and 2d) and N-tosyloxycarbamates (2b and 2e).
The results are summarized in Table 3. The organocatalytic
asymmetric aziridination reactions when using 2a and 2d as
the reactants were highly chemo- and enantioselective and
the corresponding Cbz- and Boc-protected 2-formylaziri-
dines 3 were obtained in good to high yields with 4:1–10:1
d.r. and 84–99% ee. Simple linear a,b-unsaturated aldehydes
gave the corresponding products in high yields with excel-
Leaving-group and condition screen: We next screened dif-
ferent substituents on the O atom of N-carbobenzyloxy
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Catalytic Asymmetric Aziridination of a,b-Unsaturated Aldehydes
FULL PAPER
Table 2. Leaving-group and condition screen for the aziridination between 1a and 2.[a]
ploying 2a and 2d as the nitro-
gen source with the use of 2b
and 2e, it became clear that the
corresponding products 3 are
assembled with higher diaste-
reomeric ratios (entries 11–14,
18) except when aldehyde 1j
was employed as the substrate
(entries 15–16).
The aminocatalytic azirdidi-
nation of cinnamic aldehyde de-
rivatives were also investigated
by using 2a–e as “nitrene
equivalents” and amine 10 as
the catalyst. To our delight, the
reaction was productive when
benzyl N-tosyloxycarbamate 2b
or tert-butyl N-tosyloxycarba-
mate 2e were umployed as the
“nitrene equivalents”. In fact,
the corresponding formyl alde-
hydes 3 with an aryl moiety
were isolated in moderate to
high yields with high d.r. and ee
values ranging from 95–99%
(Table 4). The ratio between
products 3/4 was also high. For
example, substrates bearing an
electron-withdrawing group at
the aryl moiety gave the corre-
Entry
R
LG
Base
Solvent
T [8C]
t [h]
Conv. [%][b]
d.r.[c]
ee [%][d]
1
2
3
4
5
6
7
8
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Boc
Boc
Boc
OAc (2a)
OAc (2a)
OTs (2b)
OTs (2b)
OAc (2a)
OTs (2b)
OMs (2c)
OTs (2b)
OTs (2b)
OTs (2b)
OTs (2b)
OTs (2b)
OTs (2b)
OTs (2b)
OTs (2b)
OTs (2b)
OTs (2b)
OTs (2e)
OTs (2e)
OTs (2e)
–
–
–
–
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
toluene
CH2Cl2
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
RT
40
RT
40
RT
RT
RT
Rt
3
0.5
3
86
100
11
32
48
100 (78)
58
78
100
40
61
90
64
100(67)
84(58)
63(45)
60(41)
100(84)
96(74)
88(69)
9:1
5:1
99
96
n.d.
n.d.
98
97
95
97
94
94
96
99
96
96
98
97
97
99
99
98
20:1
20:1
3:1
15:1
20:1
7:1
1.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1.6
5
16
16
0.67
5
8
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
Et3N
Na2CO3
K2CO3
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
9
Rt
Rt
8:1
5:1
10
11
12
13[e]
14[f]
15[g]
16[h]
17[i]
18[j]
19[k]
20[l]
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
15:1
11:1
10:1
7:1
10:1
10:1
10:1
10:1
7:1
8:1
[a] Experimental conditions: A mixture of 2 (0.30 mmol), aldehyde 1a (0.25 mmol), catalyst 10 (20 mol%),
and base (3 equiv) in 1.0 mL CHCl3 was stirred for the time shown in the table. [b] Conversion into product
1
3a as determined by H NMR spectroscopic analysis and the value in parentheses is the isolated yield. [c] De-
1
termined by H NMR spectroscopic analysis. [d] Determined by chiral-phase HPLC analysis after reduction to
the corresponding alcohol 3’. [e] Base (NaOAc; 1 equiv) was used. [f] Base (NaOAc; 1.5 equiv) was used.
[g] 10 mol% catalyst 10 was used. [h] 5 mol% catalyst 10 was used. [i] 2.5 mol% catalyst 10 was used. [j] Boc-
NHOTs (2e) was used and the catalyst (10) loading was 20 mol%. [k] Boc-NHOTs (2e) was used and the cat-
alyst (10) loading was 10 mol%. [l] Boc-NHOTs (2e) was used and the catalyst (10) loading was 5 mol%.
sponding products
3
with
99% ee (Table 4, entries 2–3, 5–
lent ee values (Table 3, entries 1–3, 6, 8). The reaction toler-
ated several enals 1 with different functional groups (en-
tries 4–5, 7, 9–10). For example, highly chemoselective aziri-
dination of aldehyde 1c at its less electron-rich olefin can be
accomplished by using our methodology to give the corre-
sponding product 3d in 68% yield with 6:1 d.r. and 96% ee
(entry 4). The reaction performed with 10 mol% catalyst
loading slightly reduced the yield and ee (entry 2). The orga-
nocatalytic asymmetric aziridination of enals 1 when using
N-tosyloxycarbamate 2b and 2e as the “nitrene equivalents”
were highly chemo- and enantioselective, and the corre-
sponding Cbz- and Boc-protected 2-formylaziridines 3 were
obtained in good to high yields with 5:1–19:1 d.r. and 91–
99% ee (entries 11–18). The azirdination of linear enals 1a–
b, 1e, and enal 1c with a terminal double bond at the alkyl
chain gave the corresponding products 3, respectively, with
high d.r. (10:1–15:1) and ee values (94–99%; entries 11–14,
18). The fumaric acid ethyl ester mono aldehyde 1j reacted
with both Cbz- (2b) and Boc-NHOTs (2e) providing the
corresponding aziridine products 3m and 3n in good yields
with 5:1 to 6:1 d.r. and 91% ee, respectively (entries 15–16).
The simplest linear aldehyde, acrolein (1k), was also investi-
gated and the reaction proceeded smoothly at 48C to afford
the corresponding product 3o in 77% yield with 91% ee
(entry 17). When comparing the azirdination reactions em-
6, and 10). The aminocatalytic aziridination of heteroaro-
matic enals 1 was also successful (entry 4). For substrates
bearing an electron-donating group at the aryl moiety (e.g.,
1), the corresponding products 3 and 4 were formed as de-
1
termined by H NMR spectroscopic analysis of the crude re-
action mixture; however, we were not able to isolate prod-
uct 3. For example, the aziridination of 1 gave aziridine 3x
as determined by NMR spectroscopic analysis. Unfortunate-
ly, 3x decomposed when exposed to silica-gel column chro-
matography and only 4x was isolated in 20% yield
(entry 7). (E)-3-(Naphthalen-2-yl)acrylaldehyde (1t) reacted
with both reagents 2b and 2e forming the corresponding
Cbz- and Boc-protected aziridine products 3y and 3bb, re-
spectively, according to 1H NMR spectroscopic analysis.
However, both products 3y and 3bb decomposed upon
silica gel column chromatography. However, we were able
to isolate the corresponding b-amino acid ester after apply-
ing our AHCC methodology (entries 8, 11). Moreover, the
aziridine reagent, tert-butyl N-tosyloxycarbamate 2e, gave
the corresponding product 3 with better yields relative to
benzyl N-tosyloxycarbamate 2b (entries 9–11 vs. 1, 5, 8). By-
products 4 are also synthetically useful since they can be
readily transformed into the corresponding protected a,b-
dehydroamino acids after oxidation. a,b-Dehydroamino
acids are present in biologically important natural products
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A. Cꢁrdova et al.
Table 3. Organocatalytic asymmetric aziridination of aliphatic a,b-unsaturated aldehydes 1 with 2.[a]
product 3cc in high conversion
(Table 5). Different base addi-
tives
and
solvents
were
screened (Table 5, entries 1–7)
and we found that NaOAc in
toluene were the best condi-
tions (entry 5). Increasing the
concertration of 1u from 0.25
to 0.5m gave the product 3cc in
higher yield (entry 8). It is im-
portant to note that the reac-
tion did not produce any prod-
uct if the amine catalyst is not
present (entry 9). Other diary-
lprolinol silyl ethers 12–14 were
probed and catalyst 13 with a
Entry
R
R1
Prod. Conditions A T [8C] t [h] Yield [%][b] d.r.[c] ee [%][d]
1
n-Pr (1a)
n-Pr (1a)
nBu (1b)
Cbz 3a
Cbz 3a
Cbz 3c
A1
A1
A1
40
40
40
0.5
0.5
0.5
78
68
70
4:1
4:1
5:1
96[f]
90[f]
96[f]
2[e]
3
4
Cbz 3d
A1
40
0.5
68
6:1
96[f]
5
Boc 3e
A2
40
0.4
68
5:1
92[f]
6
7
8
9
Me (1e)
Et (1g)
Boc 3 f
Boc 3g
Cbz 3h
Cbz 3i
A2
A2
A1
A1
18
40
40
40
5
54
60
60
62
5:1
5:1
5:1
5:1
90
98
0.4
0.6
0.5
97[f]
84
TES group gave
a similiar
result (full conversion and
93% ee) relative to catalyst 10
(entry 10). However, the enan-
tioselectivity of the reaction de-
creased when catalysts 12 and
14 were employed (entries 11–
12). Performing the aminocata-
lytic reaction at a lower temper-
ature (48C) and reducing the
amount of base additive
(1.5 equiv) gave 3cc in 88%
yield and 94% ee (entry 13).
With these results in hand, we
decided to investigate the scope
of the aziridination of a-substi-
10
Cbz 3k
A1
40
0.4
66
7:1
92
11
12
13
n-Pr (1a)
nBu (1b)
Me (1e)
Cbz 3a
Cbz 3c
Cbz 3l
A3
A3
A3
18
18
18
0.5
1
0.5
72
65
65
15:1
15:1
15:1
97[f]
97[f]
95
14
Cbz 3d
A3
18
0.5
84
10:1
94[f]
15
16
17
18
CO2Et (1j)
CO2Et (1j)
H (1k)
Cbz 3m
Boc 3n
Cbz 3o
Boc 3b
A3
A4
A3
A4
18
18
4
0.67
0.67
0.5
57
67
77
84
5:1
6:1
–
91[f]
91[g]
91
nPr (1a)
18
0.67
10:1
99[g]
19[h]
Boc 3p
Cbz 3h
A4
A3
18
18
5.5
0.4
73
74
7:1
99
98[f]
20
Et (1g)
13:1
21
Boc 3e
Cbz 3a
A4
A3
18
18
0.4
0.5
68
70
10:1
19:1
97
22[i]
nPr (1a)
97[f]
[a] Experimental conditions: A1: A mixture of Cbz-NHOAc (2a) (0.30 mmol), aldehyde 1a (0.25 mmol), and
catalyst 10 (20 mol%) in 1.0 mL CHCl3 was stirred for the time shown in the table. A2: A mixture of Boc-
NHOAc (2d) (0.30 mmol), aldehyde 1a (0.25 mmol), and catalyst 10 (20 mol%) in 1.0 mL CHCl3 was stirred
for the time shown in the table. A3: A mixture of Cbz-NHOTs (2b) (0.25 mmol), aldehyde 1 (0.30 mmol), cat-
alyst 10 (20 mol%), and NaOAc (3 equiv) in 1.0 mL CHCl3 was stirred for the time shown in the table. A4: A
mixture of Boc-NHOTs (2e) (0.25 mmol), aldehyde 1 (0.30 mmol), catalyst 10 (20 mol%), and NaOAc
(3 equiv) in 1.0 mL CHCl3 was stirred for the time shown in the table. [b] Isolated yield of pure product 3
tuted-a,b-unsaturated
alde-
hydes 1 when using amine cata-
lyst 10 and NaOAc as the add-
tive in toluene at 48C (Table 6).
The aminocatalytic aziridina-
tion with Cbz- (2b) and Boc-
NHOTs (2e) were efficient,
highly enantioselective, and
proceeded smoothly to give the
corresponding Cbz- and Boc-
protected terminal aziridine
products 3cc–ll in good yields
1
after silica-gel column chromatography. [c] Determined by H NMR spectroscopic analysis. [d] Determined by
chiral-phase HPLC analysis. [e] 10 mol% of catalyst 10 was used. [f] Determined by chiral-phase HPLC analy-
sis after reduction to the corresponding alcohol 3’ (see the Experimental Section). [g] Determined by chiral-
phase HPLC analysis after reduction and benzoylation of 3n and 3b to the corresponding product 3n’’ and
3b’’, respectively (see the Experimental Section). [h] 5 mol% catalyst 10 was used. [i] Reaction performed at
1 mmol scale of enal 1.
(e.g., peptides, antibiotics and enzymes) and useful com-
pounds for synthetic peptide design.[31]
with 91–96% ee (Table 6, entries 1–10). The chiral amine 10-
catalyzed aziridination was successful for several a-methyl-
ene aldehydes 1 with different functional groups (entries 6–
9). For example, the highly enantioselective aziridination of
aldehyde 1x at its electron-deficient olefin was accom-
plished and gave the corresponding terminal aziridines 3hh
and 3ii in 65 and 73% yields with 91 and 92% ee, respec-
tively (entries 6–7). Asymmetric aminocatalytic aziridination
of enal 1y with a Bz-protected terminal hydroxy group at
the a-alkyl substituent (1y) furnished products 3jj and 3kk
in 75 and 90% yields with 92 and 94% ee, respectively (en-
tries 8–9). Moreover, the aziridinating reagent TsNHOTs
(2 f) was also employed under the same reaction conditions
Organocatalytic asymmetric aziridination of a-substituted
a,b-unsaturated aldehydes: Encouraged by the above suc-
cess, we became intrigued as to whether functionalized aziri-
dines containing an a-tertiary amine stereocenter could be
synthesized by a chiral amine-catalyzed reaction between a-
substituted a,b-unsaturated aldehydes 1[32–33] and a suitable
nitrogen source 2. To our delight, when using 2b as the re-
agent, the aziridination of 1u proceeded smoothly in the
presence of chiral pyrrolidine catalysts (10, 12, and 14) to-
gether with a base additive affording the corresponding
7908
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Chem. Eur. J. 2011, 17, 7904 – 7917

Catalytic Asymmetric Aziridination of a,b-Unsaturated Aldehydes
FULL PAPER
Table 4. Organocatalytic asymmetric aziridination of aromatic a,b-unsaturated aldehydes 1 with benzyl N-tol-
uenesulfonyloxycarbamate 2b.[a]
tioselective azirdination of dis-
ubstituted-a,b-unsaturated alde-
hydes 1. If successful, this type
of reaction would generate azir-
idines with adjacent tertiary
and quaternary stereocenters a
challenging task in organic syn-
thesis. Initially we investigated
the chiral amine 10-catalyzed
azirdination reaction between
aldehyde 1aa and N-Boc-hy-
droxylamine derivative 2e. The
reaction gave the corresponding
product in high yield and good
d.r. but low ee.[35] To our de-
light, we found that the reac-
tion with TsNHOTs (2 f) as the
“nitrene equivalent” gave the
corresponding aziridines 3nn in
61% yield with 8:1 d.r. and
99% ee (Table 7, entry 1). Thus,
the exploration of the reaction
for a set of aliphatic disubstitut-
ed enals 1 was performed. The
reaction was highly enantiose-
lective and gave the corre-
sponding aziridines 3oo–rr with
adjacent tertiary and quaterna-
ry stereocenters in high yields
with 10:1–25:1 d.r. and 99% ee
(entries 2–5). For example, the
aldehyde 1bb with three double
bonds was enantioselectively
aziridinated to give aziridine
3oo with two terminal double
bonds in 77% yield with 10:1
Entry
1
R
R1
Prod.
t [h]
Ratio 3/4[b]
Yield [%][b]
52
d.r.[c]
19:1
ee [%][d]
Cbz
3r
0.5
10:1
99[g]
2[f]
3
Cbz
Cbz
3s
3t
2
>20:1
>20:1
60
40
18:1
19:1
99[g]
97[g]
0.5
4
5
Cbz
Cbz
3u
3v
0.5
0.5
4:1
6:1
64
64
15:1
15:1
95
99
6
Cbz
3w
0.5
4:1
44
10:1
99[g]
7
8
Cbz
Cbz
3x
3y
0.67
0.67
3:1
4:1
55[h]
25[i]
12:1
19:1
n.d.
95[i]
9
Boc
Boc
Boc
3z
1
25:1
20:1
9:1
63
72
15:1
19:1
19:1
99
10
11
3aa
3bb
1
99[g]
99[i]
1.5
38[i]
12[j]
Cbz
3r
0.5
10:1
69
19:1
99[g]
[a] Experimental conditions: A mixture of 2b (0.30 mmol), aldehyde 1 (0.25 mmol), catalyst 10 (20 mol%),
and NaOAc (3 equiv) in 1.0 mL CHCl3 was stirred at 188C for the time shown in the table. [b] The ratio of 3
to 4 was determined by 1H NMR spectroscopic analysis. [c] Isolated yield of pure product 3 after silica-gel
column chromatography. [d] Determined by 1H NMR spectroscopic analysis. [e] Determined by chiral-phase
HPLC analysis. [f] Reaction was run at 48C. [g] Determined by chiral-phase HPLC analysis after reduction to
the corresponding alcohol 3’ (see the Experimental Section). [h] Conversion into product 3x as determined by
1H NMR spectroscopic analysis and 20% of compound 4x was isolated. [i] Yield and ee were obtained after
converting into the corresponding protected b-amino acid ester derivative 16 in the presence of carbene cata-
lyst (NHC-2, the structure can be seen from below, in Table 8). [j] Reaction performed at a 1 mmol scale of
enal 1.
and the corresponding product 3mm was obtained in 92%
yield with 84% ee (entry 11). Based on the above results, we
also investigated if protected diaryl prolinols could catalyze
the catalytic epoxidation of a-monosubstituted enals.[33c]
Thus, similar conditions as described in Table 6 were investi-
gated for the enantioselective epoxidation of a-substituted
enal 1u with H2O2 (Scheme 2).[34] The chiral amine 10-cata-
lyzed reaction was successful and the corresponding epoxide
15 was isolated in 59% yield with 86% ee [Eq. (6)].
Scheme 2. Two-step one-pot asymmetric synthesis of protected b-amino
acid ester derivative 16a. DIPEA=N,N’-diisopropylethylamine.
d.r. and 99% ee (entry 2). The asymmetric aziridination of
aldehyde 1dd gave the corresponding nearly enantiomeri-
cally pure aziridine 3qq in 79% yield (>25:1 d.r. and
99% ee, entry 4). The reaction was also highly enantioselec-
tive for the catalytic azirdination of a-methyl-cinamic alde-
hyde 1 ff (entry 6). Thus, both mono- and disubstituted a,b-
With the experience gathered until now, we decide to un-
dertake the challenge of developing an aminocatalytic enan-
Chem. Eur. J. 2011, 17, 7904 – 7917
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7909

A. Cꢁrdova et al.
Table 5. Condition screening of the asymmetric aziridination of a-substi-
tuted a,b-unsaturated aldehydes 1u with benzyl N-toluenesulfonyloxycar-
bamate 2b.[a]
Table 7. The asymmetric aziridination of a,b-disubstituted-a,b-unsaturat-
ed aldehydes 1 with 2 f (TsNHOTs).[a]
Entry
1
1
t [h] Prod. Yield [%][b] d.r.[c]
ee [%][d]
74 3nn
68 3oo
66 3pp
72 3qq
61
77
84
79
8:1
99
2
3
4
10:1
99
99
99
Entry Catalyst Solvent Additive t [h] Conv. [%][b] ee [%][c]
>25:1
>25:1
1
2
3
4
5
6
7
10
10
10
10
10
10
10
10
–
13
12
14
10
CHCl3
CHCl3
CHCl3
CHCl3
toluene NaOAc
CH2Cl2
EtOH
toluene NaOAc
toluene NaOAc
toluene NaOAc
toluene NaOAc
toluene NaOAc
toluene NaOAc
NaOAc
K2CO3
Et3N
17
17
16
16
17
19
17
17
17
16
16
20
16
69
69
66
46
88
7
25
14
94
84
59
92
–
93
72
76
94
Na2CO3
100 (49)[d]
5
66 3rr
65 3ss
66 3pp
83
55
78
17:1
99
98
99
NaOAc
NaOAc
54
100
8[e]
9
10
11
12[f]
13[e,g]
100 (68)[d]
6
>25:1
>25:1
0
100
43
7[e]
100
[a] Experimental conditions: A mixture of aldehyde 1 (0.25 mmol), 2
(0.30 mmol), NaOAc (0.375 mmol), and catalyst 10 (20 mol%) in toluene
(0.5 mL) was stirred at 48C for the time shown in the table. The product
3 was purified by column chromatography. [b] Isolated yield of pure
product 3 after silica-gel column chromatography. [c] Determined by
crude 1H NMR spectroscopic analysis. [d] Determined by chiral-phase
HPLC analysis. [e] The reaction was performed at a 1 mmol scale of enal
1.
100 (88)[d]
[a] Experimental conditions: A mixture of 2b (0.30 mmol), aldehyde 1u
(0.25 mmol), additive (0.75 mmol), and catalyst (20 mol%) in 1.0 mL sol-
vent was stirred for the time shown in the table. [b] Conversion of 1u as
determined by 1H NMR spectroscopic analysis. [c] Determined by chiral-
phase HPLC analysis. [d] Isolated yield in parenthesis. [e] Reaction was
run in 0.5 mL solvent. [f] Catalyst 20 (10 mol%) was used. [g] Reaction
run at 48C.
unsaturated aldehydes can be aziridinated in a catalytic
asymmetric fashion by our methodology.
Table 6. The asymmetric aziridination of a-substituted-a,b-unsaturated
aldehydes 1 with 2b (Cbz-NHOTs) and 2e (Boc-NHOTs).[a]
One-pot enantioselective AHCC and short asymmetric syn-
thesis of amino acid derivatives: The employment of N-he-
trocyclic carbene (NHC) catalysis is a powerful method for
the ring-opening of three-membered rings as shown by
Bode and co-workers (e.g., epoxides, aziridines, and cyclo-
propanes).[36–37] Recently, we developed the first combina-
tion of asymmetric AHCC for the one-pot three-component
synthesis of b-hydroxy esters and b-malonate esters with
high ee values.[38] This was accomplished by first performing
aminocatalytic enantioselective epoxidations or cyclopropa-
nations of enals followed by an in situ ring-opening/oxida-
tion/esterification sequence by a N-heterocyclic carbene cat-
alyst. With these results in mind, we embarked on the devel-
opment of AHCC for the one-pot three-component synthe-
sis of Cbz- or Boc-protected b-amino acid esters
(Scheme 2). In initial experiments, we found that the se-
quential one-pot combination of chiral amine 10 and in situ
generated NHC catalyst from thiazolium salt NHC-1,[36]
gave the corresponding b-amino acid ester 16a in 63% yield
by starting from 2-hexenal 1a, acetyl carbamate 2a, and eth-
anol (3 equiv). Removal of the Cbz group by hydrogenolysis
with 10 wt.% Pd/C gave the corresponding b-amino acid
ester 17a. The absolute configuration of the aziridine prod-
Entry
R1
R
Product
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
Bn (1u)
Bn (1u)
n-hexyl (1v)
n-pentyl (1w)
n-pentyl (1w)
Cbz
Boc
Cbz
Cbz
Boc
Cbz
3cc
3dd
3ee
3 ff
3gg
3hh
88
89
69
64
67
65
94
96
95
95
95
91
7
8[d]
Boc
Cbz
Boc
3ii
73
75
90
92
92
94
3jj
3kk
9
10
nBu (1v)
n-pentyl (1w)
n-hexyl (1v)
Boc
Ts
Cbz
3ll
3mm
3ee
81
92
60
96
84
95
11
12[e]
[a] Experimental conditions: A mixture of aldehyde 1 (0.25 mmol), 2
(0.30 mmol), NaOAc (0.375 mmol), and catalyst 10 (20 mol%) in toluene
(0.5 mL) was stirred at 48C for 16 h. The product 3 was purified by
column chromatography. [b] Isolated yield of pure product 3 after silica-
gel column chromatography. [c] Determined by chiral-phase HPLC anal-
ysis. [d] Reaction was run at RT. [e] Reaction performed at a 1 mmol
scale of enal 1.
7910
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Chem. Eur. J. 2011, 17, 7904 – 7917

Catalytic Asymmetric Aziridination of a,b-Unsaturated Aldehydes
FULL PAPER
Table 8. One-pot enantioselective synthesis of protected b-amino acid ester derivative 16 by AHCC.[a]
uct 3 was assigned to be R at
C3 by comparison of the optical
rotation power of compound
17a with literature data ([a]2D5 =
+10.9 (c=0.5 in H2O); lit.[39]
(S)-17a: [a]2D5 =À10.7 (c=2.1 in
H2O)).
Entry
R
R1
R2
Cat. 10 [mol%]
t [h]
Prod.
Yield [%][b]
ee [%][c]
1
2
n-Pr (1a)
Ph (1m)
Cbz
Cbz
Me
Me
20
20
0.5
0.5
16b
16m
62
54
93
96
We next investigated the
AHCC protocol by using Rovis
NHC catalyst (2-(perfluoro-
phenyl)-6,7-dihydro-5H-pyrro-
lo[2,1-c,1,2,4]triazol-2-ium tetra-
3
Boc
Me
5
8
16l
73
93
4
5
6
Boc
Cbz
Boc
Me
Me
Me
5
20
20
8
16d
16t
80
25
38
92
95
99
fluoroborate)[40]
precursor
0.7
1
NHC-2 (Table 8). The one pot
AHCC procedure was highly
enantioselective and the corre-
sponding N-Boc or N-Cbz-pro-
tected b-amino acid esters 16
were obtained in moderate to
high yields with 92–99% ee
(Table 8). The NHC catalyst
generated in situ from NHC-2
was efficient and only 3 mol%
was needed. When Boc-NHOTs
2e was used as the nitrogen
substrate the catalyst loading of
10 could be reduced to
5 mol%. For example, the one-
pot catalytic sequence between
16tt
7
8
9
10
nPr (1a)
nPr (1a)
nPr (1a)
Ph (1m)
Cbz
Cbz
Cbz
Cbz
Me[d]
Et[d]
20
20
20
20
0.5
0.5
0.5
0.5
16b
16a
16c
16m
62
69
62
46
95
94
94
94
Bn[d]
Me[d]
11
Boc
Cbz
Me[d]
Me[d]
5
8
16d
16b
77
64
92
95
12[e]
nPr (1a)
20
0.5
[a] Experimental conditions: A mixture of aldehyde 1 (0.25 mmol), 2 (0.30 mmol), NaOAc (0.75 mmol), and
catalyst 10 (5–20 mol%) in CHCl3 (1.0 mL) was stirred at RT for the time shown in the table. Then, methanol
(1.0 mL) and 2-(perfluorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c,1,2,4]triazol-2-ium tetrafluoroborate (3 mol%)
was added to the reaction mixture. The resulting solution was stirred for 16 h at room temperature. After that,
the solvent was evaporated and product 16 was purified by flash chromatography. [b] Isolated yield of pure
product 16 after silica-gel column chromatography. [c] Determined by chiral-phase HPLC analysis. [d] Alcohol
(3 equiv) was used. [e] The reaction was performed at a 1 mmol scale of the enal 1.
aldehydes 1l or 1d, 2e, and MeOH gave the corresponding
b-amino acid esters 16l and 16d in 73 and 80% yield and 93
and 92% ee, respectively (Table 8, entries 3–4). It is note-
worthy that the one-pot enantioselective AHCC sequence
enabled the synthesis of b-amino acid derivatives even
though enals 1 with a b-aryl moiety were used as substrates.
For example, b-amino acid esters 16t and 16tt were isolated
in low yields but with excellent ee values (95 and 99%, re-
spectively) when (E)-3-(naphthalen-2-yl)acrylaldehyde (1t)
was employed as the starting material. The alcohol compo-
nent could also be varied and reduced to three equivalents
without affecting the yields and stereoselectivity of the reac-
tion.
this methodology. Moreover, the possibility of performing a
one-pot asymmetric trans-aminohydroxylation of enal 1a
was investigated [Eq. (8)].[26c] It was successful in a two-step
sequence involving the organocatalytic enantioselective azir-
idination followed by a Payne-type rearrangement with
NaOMe (2.2 equiv) by starting from trans-hex-2-enal (1a) to
give trans-3-amino-2-hydroxy aldehydes 19b in moderate
overall yield but excellent stereoselectivity [>19:1 d.r. and
99% ee, Eq. (8)].
As mentioned before aziridines are present in natural
products and useful synthons for total synthesis.[1] Thus, we
decided to investigate the short expeditious formal total syn-
thesis
of
(2S,3S)-(+)-aziridine-2,3-dicarboxylic
acid
[Eq. (7)].[41] It was successfully executed by oxidation and in
situ esterification of the b-formyl azirdine product, which
had been generated by the chiral amine 10-catalyzed aziridi-
nation of (E)-ethyl 4-oxobut-2-enoate 1j in methanol. In
fact, this protocol gave the protected natural product
(2S,3S)-(+)-aziridine-2,3-dicarboxylic acid derivative 18k in
33% yield (two steps) with >19:1 d.r.[41a,b] Interestingly,
transesterification occurred during the one-pot oxidation
esterification step.
Determination of the absolute configurations: The absolute
configuration of linear aziridines 1 was determined by syn-
thesis of 17a (Scheme 2). Thus, the aziridine reaction of
Acid ester 18m, which is useful in total synthesis,[42] was
also expeditiously synthesized in moderate yield by using
Chem. Eur. J. 2011, 17, 7904 – 7917
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www.chemeurj.org
7911

A. Cꢁrdova et al.
Figure 2. ORTEP picture of (2S,3R)-2-ethyl-3-propyl-1-tosylaziridine-2-
carbaldehyde (3nn).
hydes enals 1 by using amine (S)-10 as the catalyst gives
access to (2S,3R)-2-formylaziridines 3.
Mechanism: Based on the absolute configuration of the azir-
idine products 3, synthesized by the aminocatalytic reaction
between hydroxyl amines 2 and linear, monosubstituted,
and disubstituted-a,b-unsaturated aldehydes 1, we were able
to propose
a unified mechanism for their formation
(Scheme 3, cycle A). Thus, initial reversible iminium forma-
tion between enals 1 and the chiral pyrrolidine derivative
gives the iminium intermediate I. Efficient shielding of the
Si face (R1 =alkyl) of the iminium intermediate I leads to
nucleophilic aza-conjugate addition of 2 to the b-carbon
atom at the Re face (R1 =alkyl) of iminium intermediate I
and generates the chiral enamine intermediate II. Next, the
generated chiral enamine intermediate II performs a 3-exo-
tet nucleophilic attack on the electrophilic nitrogen atom
Figure 1. a) ECD spectra calculated for the (2R)-3cc and the optimized
geometry. b) ECD spectra calculated for the (2S)-3cc and the optimized
geometry. c) Experimental (full trace) ECD spectra of compound 3cc.
linear enals 1 gives access to (2S,3R)-2-formylaziridines 3 by
using amine catalyst (S)-10. The absolute configuration of
terminal aziridines 3 obtained by enantioselective aziridina-
tion of monosubstituted a,b-unsaturated aldehydes 1 was as-
signed by means of TD-DFT
calculations of the electronic
dichroism (ECD) spectra of
3cc (Figure 1).[43] The DFT cal-
culations of the S enantiomer
of 3cc matched with the experi-
mental CD spectra of 3cc
(Figure 1). Thus, the absolute
configuration of 3cc at C-2 is
assigned S.
The aboslute configuration
of the aziridine products 3 syn-
thesized from disubstituted-
a,b-unsaturated aldehydes
1
was determined by X-ray anal-
ysis of 3nn.[44] The absolute
configuration of product 3nn
was 2S,3R (Figure 2). Thus, the
aziridine reaction of disubsti-
tuted-a,b-unsaturated
alde- Scheme 3. Proposed reaction pathway for the enantioselective aziridination of enals 3.
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Chem. Eur. J. 2011, 17, 7904 – 7917

Catalytic Asymmetric Aziridination of a,b-Unsaturated Aldehydes
FULL PAPER
from its Re face and the leaving group (R3OH) is released.
The intramolecular ring closure pushes the equilibrium for-
ward and makes this step irreversible and gives iminium in-
termediate III. It is noteworthy that it is this cyclization
step, which dictates the stereoselectivity for the aminocata-
lytic aziridination of a-substituted enals 1 (R1 =H). Subse-
quent hydrolysis of the iminium intermediate III gives the
corresponding aziridine product 3 and releases the amine
catalyst. Thus, the protected (S)-prolinol derivatives catalyz-
es the aziridination of linear- and disubstituted-a,b-unsatu-
rated aldehydes 1 with hydroxylamines 2 to give the corre-
sponding (2S,3R)-2-formylaziridines 3. The reactions with a-
substituted enals (R1 =H, R2 =alkyl) gave the corresponding
(S)-aziridines 3.
In the case of the aminocatalytic enantioselective aziridi-
nation of cinnamic aldehyde derivatives 1, the correspond-
ing aziridine products could also rearrange to form a-
amino-a,b-unsaturated aldehydes 4 (Scheme 3, cycle B). In
fact, this type of base-catalyzed rearrangement has been
previously observed in aminocataytic enantioselective cyclo-
propanation reactions between enals and bromomalo-
nates.[33a,45] As described vide supra, iminium intermediate
III is generated by the first catalytic cycle (cycle A). It can
next undergo hydrolysis to give the corresponding aziridine
product 3 or enter a second catalytic cycle in which a base-
promoted formation of enamine intermediate V occurs
through iminium intermediate IV (cycle B). Iminium inter-
mediate IV can also be generated by in situ condensation
between the chiral amine catalyst and the aziridine product
3. In fact, mixing the cinnamic aldehyde derived product 3r
together with catalyst 10 in the presence of base gave 4r.
Next, ring-opening of V gives iminium intermediate VI. Pro-
tonation of intermediate VI and hydrolysis of iminium VII
liberates the chiral-amine catalyst 10 and gives the corre-
sponding a-amino-a,b-unsaturated aldehyde 4. Our experi-
mental results indicate that cinnamic aldehyde derivatives
with an electron-donating substituent give more of product
4 relative to the ones with electron-withdrawing groups.
The mechanistic proposal for the one-pot three-compo-
nent reaction between a,b-unsaturated aldehydes 1, hydrox-
ylamines 2, and an alcohol, which gave b-amino acid ester
derivatives 16 by AHCC is shown in Scheme 4. The one-pot
tandem reaction starts with a chiral amine-catalyzed highly
diastereo- and enantioselective aziridinnation of enal 1 to
form aziridine 3 (Scheme 3). Next, the in situ generated N-
heterocyclic carbene catalyst performs a nucleophilic attack
at the aldehyde moiety of b-formyl-azirdine 3 and zwitter-
Scheme 4. Possible mechanism of the one-pot three-component reaction
between an enal 1, hydroxylamine 2, and an alcohol.
amino acid residues in peptides, with no enantioselectivity.
Thus, we investigated the one-pot cascade reaction sequence
by starting with aldehyde 1w [Eq. (9)]. The transformation
with racemic catalyst 10 gave the corresponding b2-amino
acid ester 16uu in 69% yield. The same transformation with
(S)-10 as the catalyst afforded nearly racemic 16uu (<
5% ee).[47] However, the intermediate aziridine 3 ff was
formed with 95% ee (Table 6, entry 4). Thus, no stereoselec-
tive protonation occurred in cycle C when a-monosubstitut-
ed enals 1 were employed as substrates. However, stereose-
lective protonation occurred when performing the AHCC
sequence employing enal 1cc as the substrate [Eq. (10)].
À
ionic species VIII is formed. Subsequent, C N bond cleav-
age/ring opening occurs and intermediate IX is generated.
Activated intermediate XI is formed by keto–enol tautome-
rization via intermediates IX and X.[36,38,40b] Final transesteri-
fication by the alcohol component gives the corresponding
b-amino acid ester 16 and releases the carbene catalyst.
According to the proposed mechanism for the one-pot as-
sembly of b-amino acid esters 16 (Scheme 4). The reaction
with a-monosubstituted enals 1 should give b2-amino acid
derivatives,[46] which are important naturally occurring
Conclusion
In summary, we have disclosed the development, scope, and
application of the highly enantioselective aziridination of
Chem. Eur. J. 2011, 17, 7904 – 7917
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7913

A. Cꢁrdova et al.
using Applied photophysics Pro-Data viewer 4.0.17. De values are ex-
a,b-unsaturated aldehydes. The study shows that by careful-
ly designing the substituents of a hydroxylamine derivative
it is possible to employ it as a substrate for the highly enan-
tioselective aziridination of a,b-unsaturated aldehydes in the
presence of a simple chiral amine catalyst. The aminocata-
lytic aziridination of linear a,b-unsaturated aldehydes was
highly diastereo- and enantioselective and enabled the
asymmetric synthesis of the corresponding b-formyl aziri-
dines with up to >19:1 d.r. and 99% ee. The aminocatalytic
aziridinaton of a-monosubstituted enals gave the corre-
sponding terminal aziridines with a quaternary stereocenter
in high yields and up to 99% ee. It is noteworthy that ami-
nocatalytic aziridination of disubstituted-a,b-aldehydes was
highly stereoselective (8:1–>25:1 d.r., 99% ee) and gave
the corresponding azirdine products bearing two adjacent
tertiary and quaternary stereocenters. A highly enantioselec-
tive one-pot three-component asymmetric synthesis of b-
amino acid esters was also developed. The reaction was ach-
ieved by the one-pot combination of chiral AHCC. We also
demonstrated that the catalytic aziridination reaction could
be applied to the formal total synthesis of naturally occur-
ring azirdines. The mechanisms and stereochemistry of the
reactions are also discussed. Future research will include de-
velopment of novel one-pot cascade catalysis reactions by
using a,b-unsaturated aldehydes and hydroxylamine deriva-
tives as substrates, application of the optically active aziri-
dine products in total- and diversity-oriented synthesis (e.g.,
metal-catalyzed stereoselective cycloadditions and multi-
componet reactions), and further development of related or-
ganocatalytic aziridination reactions.
pressed as LmolÀ1 cmÀ1
.
Representative procedure for the aziridination between benzyl N-acetox-
ycarbamate 2a or tert-butyl N-acetoxycarbamate 2d and a,b-unsaturated
aldehyde 1: a,b-Unsaturated aldehyde
1 (1.0 equiv, 0.25 mmol) was
added to a stirred solution of catalyst 10 (20 mol%) and benzyl N-ace-
toxycarbamate 2a or tert-butyl N-acetoxycarbamate 2d (1.2 equiv,
0.30 mmol) in CHCl3 (1.0 mL) at 408C. The reaction was vigorously
stirred for the reported time. Next, the reaction was directly loaded upon
a silica gel column and immediate chromatography (pentane/EtOAc or
toluene/EtOAc) gave the corresponding aziridine product 3.
Representative procedure for the aziridination between benzyl N-tosyl-
carbamate 2b or tert-butyl N-tosylcarbamate 2e and aliphatic a,b-unsatu-
rated aldehyde 1: a,b-Unsaturated aldehyde 1 (1.2 equiv, 1.2 mmol) and
NaOAc (3.0 mmol, 3 equiv) were added to a stirred solution of catalyst
10 (20 mol%) and benzyl N-tosylcarbamate 2b or tert-butyl N-tosylcar-
bamate 2e (1.0 equiv, 1.0 mmol) in CHCl3 (4.0 mL) at room temperature.
The reaction was vigorously stirred for the reported time. Next, the reac-
tion was directly loaded upon a silica gel column and immediate chroma-
tography (pentane/EtOAc or toluene/EtOAc) gave the corresponding
aziridine product 3.
AHCTUNGTERG(NNUN 2S,3R)-Benzyl 2-formyl-3-propylaziridine-1-carboxylate (3a): Colorless
oil; 1H NMR (400 MHz, CDCl3): d=9.13 (d, J=4.8 Hz, 1H), 7.38–7.34
(m, 5H), 5.19 (d, J=12.8 Hz, 1H), 5.14 (t, J=12.8 Hz, 1H), 3.01–2.98 (m,
1H), 2.86–2.78 (m, 1H), 1.67–1.42 (m, 4H), 0.95 ppm (t, J=7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=195.6, 160.1, 135.8, 128.9, 128.8, 128.7,
128.6, 68.8, 47.1, 44.1, 33.0, 20.1, 13.7 ppm; HRMS (ESI): m/z: calcd for
C14H17NO3: 270.1101 [M+Na]+; found: 270.1104; [a]2D5 =À11.7 (c=1.0 in
CHCl3) for an enantiomerically enriched sample of 99% ee; the enantio-
meric excess was determined by reduction to the corresponding alcohol
by HPLC analysis in comparison with authentic racemic material (ODH-
column, n-hexane/iPrOH 95:5, l=210 nm, 1.0 mLminÀ1): tR (major enan-
tiomer)=13.7, tR (minor enantiomer)=12.2 min.
Representative procedure for the aziridination between benzyl N-tosyl-
carbamate 2b or tert-butyl N-tosylcarbamate 2e and aromatic a,b-unsa-
turated aldehydes 1: a,b-Unsaturated aldehyde 1 (1.0 equiv, 1.0 mmol)
and NaOAc (3.0 mmol, 3 equiv) were added to a stirred solution of cata-
lyst 10 (20 mol%) and benzyl N-tosylcarbamate 2b or tert-butyl N-tosyl-
carbamate 2e (1.2 equiv, 1.2 mmol) in CHCl3 (4.0 mL) at room tempera-
ture. The reaction was vigorously stirred for the reported time. Next, the
reaction was directly loaded upon a silica gel column and immediate
chromatography (pentane/EtOAc or toluene/EtOAc) gave the corre-
sponding aziridine product 3.
Experimental Section
General: Chemicals and solvents were either purchased from commercial
suppliers or purified by standards techniques. The pyrrolidine catalysts
were synthesized according to literature procedures.[1] For thin-layer
chromatography (TLC), silica gel plates Merck 60 F254 were used and
compounds were visualized by irradiation with UV light and/or by treat-
AHCTUNGTERG(NNUN 2S,3R)-Benzyl 2-formyl-3-(pyridin-3-yl)aziridine-1-carboxylate (3u):
Yellow oil; 1H NMR (400 MHz, CDCl3): d=9.49 (d, J=2.8 Hz, 1H),
8.64–8.55 (m, 2H), 7.56 (dt, J=2.0, 8.0 Hz, 1H), 7.40–7.28 (m, 6H), 5.20
(dd, J=12.0, 20.0 Hz, 2H), 3.88 (d, J=2.4 Hz, 1H), 3.38 ppm (t, J=
2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=193.7, 159.5, 150.3, 148.9,
135.1, 133.9, 130.6, 129.0, 128.9, 128.9, 123.9, 69.3, 49.6, 44.0 ppm; HRMS
(ESI): m/z: calcd for C16H15N2O3: 283.1077 [M+Na]+; found: 283.1077;
[a]2D5 =À56.0 (c=0.5 in CHCl3) for an enantiomerically enriched sample
of 95% ee; the enantiomeric excess was determined by chiral HPLC with
an AD-column (n-hexane/iPrOH 85:15, l=210 nm): 1.0 mLminÀ1, tR
(major enantiomer)=26.0, tR (minor enantiomer)=12.6 min.
ment with a solution of ammoniummolybdate (100 g), CeACHTNUGTRNEG(UN SO4)2 (2 g) and
10% H2SO4 (1 L) followed by heating or by treatment with a solution of
potassium permanganate (3 g), K2CO3 (20 g), 5% aq. NaOH (5 mL) and
water (300 mL) followed by heating. Flash chromatography was per-
1
formed using silica gel Merck 60 (particle size 0.040–0.063 mm), H NMR
and 13C NMR spectra were recorded on Bruker AM400 or Varian
AS400. Chemical shifts are given in
d relative to tetramethylsilane
(TMS), the coupling constants J are given in Hz. The spectra were re-
General procedure for the aziridination between benzyl N-tosyloxycarba-
mates 2b or tert-butyl N-tosyloxycarbamates 2e and a-substituted-a,b-
unsaturated aldehyde 1: a-Substituted a,b-unsaturated aldehyde 1u–aa
(1.0 equiv, 1.0 mmol), benzyl N-tosyloxycarbamate 2b or tert-butyl N-to-
syloxycarbamate 2e (1.2 equiv, 1.2 mmol) and NaOAc (1.5 mmol,
1.5 equiv) were added to a stirred solution of catalyst 10 (20 mol%) in
toluene (2.0 mL) at 08C and the resulting reaction mixture was vigorous-
ly stirred for the reported time at 48C. Next, the reaction was directly
loaded upon a silica-gel column and immediate chromatography (pen-
tane/EtOAc) furnished the corresponding aziridine products 3cc–mm.
corded in CDCl3 as solvent at room temperature, TMS served as internal
standard (d = 0 ppm) for H NMR and CDCl3 was used as internal stan-
1
dard (d = 77.16 ppm) for 13C NMR. HPLC was carried out using a
Waters 2690 Millenium with photodiode array detector. Optical rotations
were recorded on a Perkin Elmer 241 Polarimeter (d = 589 nm, 1 dm
cell). High-resolution mass (ESI) were obtained with a Bruker Micro-
TOF spectrometer. Far-UV CD measurements were made on an Applied
photophysics chirascan CD spectropolarimeter (Surrey, United Kingdom)
with a quartz cuvette with a path length of 0.1 cm. Wavelengths ranging
between 190 and 400 nm were scanned, with a 0.5 nm step resolution and
100 nm per min scan speed. The response time was 4 s, with 50 mdeg sen-
sitivity and a 1 nm band width. Measurements were conducted at 208C in
acetonitrile and the concentration was 1.43ꢃ10À4 molLÀ1. Spectra were
collected and averaged over 1–34 scans. The CD spectra were evaluated
(S)-Benzyl-2-benzyl-2-formylaziridine-1-carboxylate (3cc): Colorless oil;
1H NMR (400 MHz, CDCl3): d=8.92 (s, 1H), 7.35–7.33 (m, 3H), 7.28–
7.23 (m, 7H), 5.15 (d, J=9.6 Hz, 1H), 5.10 (d, J=9.6 Hz, 1H), 3.26 (d,
J=12.0 Hz, 1H), 3.16 (d, J=12.0 Hz, 1H), 2.70 (s, 1H), 2.40 ppm (s,
7914
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Chem. Eur. J. 2011, 17, 7904 – 7917

Catalytic Asymmetric Aziridination of a,b-Unsaturated Aldehydes
FULL PAPER
1H); 13C NMR (100 MHz, CDCl3): d=195.8, 160.2, 135.5, 135.2, 129.9,
128.7, 128.64, 128.58, 128.4, 127.1, 68.8, 50.2, 35.2, 34.2 ppm; HRMS
(ESI): m/z: calcd for C18H17NO3Na: 318.1101 [M+Na]+; found: 318.1099;
[a]2D5 =+49.7 (c=1.0 in CHCl3) for an enantiomerically enriched sample
of 92% ee; the enantiomeric excess was determined by HPLC analysis in
comparison with authentic racemic material (ODH column, n-hexane/
comparison with authentic racemic material (ODH column, n-hexane/
iPrOH 95:5, 0.5 mLminÀ1): tR (major enantiomer)=22.1, tR (minor enan-
tiomer)=23.6 min.
One-pot synthesis of b-amino acid ester derivatives 16: A mixture of al-
dehyde 1 (1.0 mmol), 2 (1.2 mmol), NaOAc (3.0 mmol), and catalyst 10
(5–20 mol%) in CHCl3 (4.0 mL) was stirred at room temperation for the
time shown in the Table 8. Then, alcohol (3 equiv) and 2-(perfluoro-
phenyl)-6,7-dihydro-5H-pyrrolo[2,1-c,1,2,4]triazol-2-ium tetrafluoroborate
(3 mol%) were added to the reaction mixture. The resulting solution was
stirred for 16 h at room temperature. After that, the solvent was evapo-
rated and product 16 was purified by flash column chromatography.
iPrOH 95:5, 1.0 mLminÀ1
, 210 nm): tR (major enantiomer)=21.5, tR
(minor enantiomer)=25.0 min.
General procedure for the aziridination reaction between 4-methyl-N-
(tosyloxy)benzenesulfonamide 2 f and a,b-disubstituted enals 1: a,b-Dis-
ubstituted enal 1aa–ee (1.0 equiv, 0.25 mmol), 4-methyl-N-(tosyloxy)ben-
zenesulfonamide 2 f (1.2 equiv, 0.30 mmol), and NaOAc (0.375 mmol,
1.5 equiv) were added to a stirred solution of catalyst 10 (20 mol%) in
toluene (0.5 mL) at room temperature and the resulting reaction mixture
was vigorously stirred for the reported time. Next, the reaction was di-
rectly loaded upon a silica-gel column and immediate chromatography
(pentane/EtOAc 10:1) furnished the aziridine product 3nn–rr.
(R)-Methyl 3-{[(benzyloxy)carbonyl]amino}hexanoate (16b): Colorless
oil; 1H NMR (400 MHz, CDCl3): d=7.37–7.31 (m, 5H), 5.18 (d, J=
8.8 Hz, 1H), 5.09 (s, 2H), 4.02–3.96 (m, 1H), 3.66 (s, 3H), 2.54 (t, J=
6.4 Hz, 2H), 1.53–1.47 (m, 2H), 1.40–1.35 (m, 2H), 0.91 ppm (t, J=
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=172.2, 156.0, 136.7, 128.6,
128.2, 127.1, 66.7, 51.8, 48.0, 39.0, 36.7, 19.5, 13.9 ppm; HRMS (ESI): m/
z: calcd for C15H21NO4Na: 302.1363 [M+Na]+; found: 302.1371; [a]D25 =+
7.5 (c=1.0 in CHCl3) for an enantiomerically enriched sample of
93% ee; the enantiomeric excess was determined by HPLC analysis in
comparison with authentic racemic material (Ad-column, n-hexane/
ACHTUNGTRENNUNG(2S,3R)-2-Ethyl-3-propyl-1-tosylaziridine-2-carbaldehyde (3nn): Color-
less oil. 1H NMR (400 MHz, CDCl3): d=9.47 (s, 1H), 7.83 (d, J=8.0 Hz,
2H), 7.36 (d, J=7.6 Hz, 2H), 3.53 (dd, J=5.6, 2.4 Hz, 1H) 2.45 (s, 3H),
2.07–1.97 (m, 1H), 1.59–1.50 (m, 1H), 1.48–1.30 (m, 4H), 1.01 (t, J=
7.2 Hz, 3H), 0.90 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=195.1, 144.7, 136.6, 129.8, 127.7, 62.7, 52.0, 29.4, 21.8, 20.8, 19.5, 13.7,
10.5 ppm; HRMS (ESI): m/z: calcd for C15H21NO3SNa: 318.1134
[M+Na]+; found: 318.1126; [a]D25 =+4.9 (c=1.0 in CHCl3) for an enan-
tiomerically enriched sample of 99% ee; the enantiomeric excess was de-
termined by HPLC analysis in comparison with the authentic racemic
material (ODH-column, n-hexane/iPrOH 98:2, 0.5 mLminÀ1, 250 nm): tR
(major enantiomer)=20.1, tR (minor enantiomer)=21.6 min.
iPrOH 95:5, 1.0 mLminÀ1
, 210 nm): tR (minor enantiomer)=13.2, tR
(major enantiomer)=15.0 min.
Preparation of (R)-ethyl 3-aminohexanoate (17a): 10% (w/w) of Pd/C
(10%) was added to a stirred solution of ester 16a (15 mg, 0.05 mmol) in
MeOH (1 mL). The reaction was stirred under 90 atm. of hydrogen over-
night. Then the crude reaction mixture was filtered through a plug of
Celite. The solvent was removed under reduced pressure to afford the
pure product 17a (8 mg, quant.).
Procedure for the epoxidation of a-substituted enal (1u): 2-Benzylacry-
laldehyde (1u) (0.25 mmol, 1 equiv) and H2O2 (0.3 mmol, 1.2 equiv) were
added to a stirred solution of catalyst 10 (20 mol%) in toluene (0.5 mL).
The reaction mixture was vigorously stirred at room temperature for
24 h. The crude reaction mixture was passed through a silica gel column
(pentane/EtOAc 10:1) to give the pure product 15 (24 mg, yield: 59%).
Compound 15: Rf =0.52 (pentane/EtOAc 6:1).
(S)-2-Benzyloxirane-2-carbaldehyde (15): Colorless oil; 1H NMR
(400 MHz, CDCl3): d=8.97 (s, 1H), 7.34–7.24 (m, 5H), 3.26 (d, J=
15.2 Hz, 1H), 3.21 (t, J=15.2 Hz, 1H), 3.03 (d, J=4.8 Hz 1H), 2.88 ppm
(d, J=4.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): 198.7, 135.0, 130.1,
128.6, 127.1, 61.5, 49.0, 33.2 ppm; HRMS (ESI): m/z: calcd for
C10H10O2Na: 185.0570 [M+Na]+; found: 185.0573; [a]2D5 =À23.9 (c=1.0
in CHCl3) for an enantiomerically enriched sample of 86% ee. The enan-
tiomeric excess was determined by HPLC analysis in comparison with
authentic racemic material (OJ-column, iso-hexane/iPrOH 98:2,
0.5 mLminÀ1, 210 nm): tR (major enantiomer)=50.5, tR (minor enantio-
mer)=58.2 min.
1
(R)-Ethyl 3-aminohexanoate (17a): H NMR (400 MHz, CDCl3): d=4.10
(q, J=7.2 Hz, 2H), 3.11–3.15 (m, 1H), 2.41 (dd, J=4.0, 15.6 Hz, 1H),
2.19 (dd, J=8.8, 15.6 Hz, 1H), 1.53 (br s, 2H), 1.29–1.37 (m, 4H), 1.21 (t,
J=7.2 Hz, 3H), 0.90 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=172.6, 60.2, 47.9, 42.6, 39.7, 19.1, 14.2, 13.9 ppm; [a]2D5 =+10.9
(c=0.5 in H2O) (lit. (S)-17a: [a]2D5 =À10.7 (c=2.1 in H2O)).[39]
General procedure for the oxidation/esterification of aziridine 3: Activat-
ed manganese dioxide (2.4 mmol, 209 mg, 17 equiv) was added to a
stirred solution of aldehyde 3 (0.14 mmol, 1 equiv) and sodium cyanide
(15 mg, 0.3 mmol, 2 equiv) in methanol (0.73 mL) at 08C.[48] After stirring
the mixture at 08C for 40 min, the reaction mixture was diluted with
ethyl acetate and filtered through a pad of Celite. The filtrated was con-
centrated in vacuo. The residue was diluted with ether, washed with satu-
rated aqueous ammonium chloride and brine, dried over sodium sulfate,
filtered, and concentrated in vacuo. The residue was purified by silica gel
column chromatography (pentane/ethyl acetate 4:1) to give the corre-
sponding ester 18.
AHCTUNGTERG(NNUN 2S,3S)-1-Benzyl 2,3-dimethyl aziridine-1,2,3-tricarboxylate (18k): Color-
Preparation of (3R)-benzyloxycarbonylamino-hexanoic acid ethyl ester
(16a): Compound 3a (25 mg, 0.1 mmol, 1.00 equiv) was added to a solu-
tion of 3-benzyl-4,5-dimethylthiazolium chloride[36] (3 mg, 0.01 mmol,
10% equiv) in CH2Cl2 (0.5 mL) at room temperature. EtOH (18 mL,
0.3 mmol, 3.0 equiv) and DIPEA (4 mL, 0.02 mmol, 20 mol%) were
added to this suspension. The resulting solution was warmed to 308C and
stirred for 15 h. The reaction mixture was treated with sat. aq. NH4Cl
(1 mL) and extracted with EtOAc (3ꢃ5 mL). The combined organic ex-
tracts were washed with brine, dried over Na2SO4, and concentrated
under reduced pressure. The residue was purified by flash chromatogra-
phy (hexane/EtOAc 3:1) to afford ester 16a (19 mg, 63%). Compound
16a: Rf =0.45 (pentane/EtOAc 3:1).
less oil; 1H NMR (400 MHz, CDCl3): d=7.38 (m, 5H), 5.18 (m, 2H),
3.76 (s, 6H), 3.45 (s, 2H), 2.19 ppm (s, 1H); 13C NMR (100 MHz, CDCl3):
d=166.8, 158.4, 135.2, 128.8, 128.7, 128.7, 69.1, 53.2, 40.3 ppm; HRMS
(ESI): m/z: calcd for C14H15O6N: 316.0792 [M+Na]+; found: 316.0794;
[a]2D5 =+5.3 (c=0.2 in CHCl3).
Typical procedure for the opening of aziridine 3 by NaOMe: NaOMe
(0.78 mmol, 2.1 equiv) in MeOH (1 mL) was added to aldehyde 3b
(79 mg, 0.37 mmol, 1 equiv) and the reaction mixture was stirred for 16 h
at room temperature. Then, the reaction was quenched by adding H2O
slowly. The mixture was extracted with ethyl acetate (3ꢃ10 mL). The
combined organic fractions were washed with brine, dried over anhy-
drous Na2SO4, filtered, and concentrated in vacuo. The residue was puri-
fied by silica gel column chromatography (pentane/ethyl acetate 3:1) to
give diester 19b in 35% yield (36 mg). Compound 19b: Rf =0.17 (pen-
tane/EtOAc 3:1).
(R)-Ethyl 3-(benzyloxycarbonylamino)hexanoate (16a): Colorless oil;
1H NMR (400 MHz, CDCl3): d=7.29–7.37 (m, 5H), 5.17 (br s, 1H), 5.09
(s, 2H), 4.12 (q, J=7.2 Hz, 2H), 3.98–4.02 (m, 1H), 2.51–2.59 (m, 2H),
1.42–1.53 (m, 2H), 1.29–1.38 (m, 2H), 1.24 (t, J=7.2 Hz, 3H), 0.91 ppm
(t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=156.0, 136.8, 129.0,
128.7, 128.6, 128.2, 66.7, 60.7, 48.1, 39.2, 36.8, 19.5, 14.3, 13.9 ppm; HRMS
(ESI): m/z: calcd for C16H23O4N: 316.1519 [M+Na]+; found: 316.1524;
[a]2D5 =+18.1 (c=1.0 in CHCl3) for an enantiomerically enriched sample
of 94% ee. The enantiomeric excess was determined by HPLC analysis in
tert-Butyl (2R,3R)-2-hydroxy-1,1-dimethoxyheptan-3-ylcarbamate (19b):
1
Colorless oil; H NMR (400 MHz, CDCl3): d=4.73 (brd, J=8.4 Hz, 1H),
4.28 (d, J=6.0 Hz, 1H), 3.77 (brs, 1H), 3.67 (s, 1H), 3.45 (s, 3H), 3.41 (s,
3H), 2.47 (s, 1H), 1.44 (s, 9H), 1.44–1.35 (m, 4H), 0.92 ppm (t, J=
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=156.1, 104.3, 79.4, 73.5,
Chem. Eur. J. 2011, 17, 7904 – 7917
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7915

A. Cꢁrdova et al.
55.1, 54.4, 51.8, 31.9, 28.5, 19.4, 14.2 ppm; HRMS (ESI): m/z: calcd for
C13H27NO5: 300.1787 [M+Na]+; found: 300.1775; [a]2D5 =+12.4 (c=0.5 in
CHCl3).
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Acknowledgements
We gratefully acknowledge the Swedish National Research council and
Wenner-Gren-Foundation for financial support. The Berzelii Center EX-
SELENT is financially supported by VR and the Swedish Governmental
Agency for Innovation Systems (VINNOVA).
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Chem. Eur. J. 2011, 17, 7904 – 7917

Catalytic Asymmetric Aziridination of a,b-Unsaturated Aldehydes
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[47] We are currently investigating this transformation by using chiral al-
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Received: January 5, 2011
Published online: May 24, 2011
Chem. Eur. J. 2011, 17, 7904 – 7917
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7917