An easy stereoselective access to β,γ-aziridino α-amino ester derivatives via Mannich reaction of benzophenone imines of glycine esters with N-sulfonyl α-chloroaldimines

Article abstract of DOI:10.1021/jo0710634

(Chemical Equation Presented) Mannich-type addition of benzophenone imine glycinates across newly synthesized N-(p-toluenesulfonyl) α- chloroaldimines afforded γ-chloro-α,β-diamino ester derivatives with moderate diastereoselectivity as separable mixtures of anti and syn diastereomers. The γ-chloro-α,β-diamino esters were efficiently cyclized under basic conditions to the corresponding β,γ-aziridino α-amino ester derivatives, representing a new class of conformationally constrained heterocyclic α,β-diamino acid derivatives. The relative configuration of the aziridines was determined via X-ray diffraction analysis. Mechanisms and intermediate transition states to explain the stereochemical outcome of the Mannich reaction with different substrates or under different conditions are proposed. The synthetic importance of the β,γ- aziridino α-amino ester derivatives is demonstrated by their conversion into the corresponding Boc-protected derivatives and ring opening reactions to α,β-diamino esters and a γ-amino α,β-unsaturated amino ester.

Full text of DOI:10.1021/jo0710634

An Easy Stereoselective Access to â,γ-Aziridino r-Amino Ester
Derivatives via Mannich Reaction of Benzophenone Imines of
Glycine Esters with N-Sulfonyl r-Chloroaldimines
Lora´nd Kiss,†,‡ Sven Mangelinckx,†,§ Reijo Sillanpa¨a¨,¶ Ferenc Fu¨lo¨p,| and
Norbert De Kimpe*,†
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent UniVersity,
Coupure Links 653, B-9000, Ghent, Belgium, Institute of Pharmaceutical Chemistry, UniVersity of Szeged,
H-6701 Szeged, P.O. Box 427, Hungary, and Department of Chemistry, UniVersity of JyVa¨skyla¨,
Fin-40351, JyVa¨skyla¨, Finland
norbert.dekimpe@ugent.be
ReceiVed May 21, 2007
Mannich-type addition of benzophenone imine glycinates across newly synthesized N-(p-toluenesulfonyl)
R-chloroaldimines afforded γ-chloro-R,â-diamino ester derivatives with moderate diastereoselectivity as
separable mixtures of anti and syn diastereomers. The γ-chloro-R,â-diamino esters were efficiently cyclized
under basic conditions to the corresponding â,γ-aziridino R-amino ester derivatives, representing a new
class of conformationally constrained heterocyclic R,â-diamino acid derivatives. The relative configuration
of the aziridines was determined via X-ray diffraction analysis. Mechanisms and intermediate transition
states to explain the stereochemical outcome of the Mannich reaction with different substrates or under
different conditions are proposed. The synthetic importance of the â,γ-aziridino R-amino ester derivatives
is demonstrated by their conversion into the corresponding Boc-protected derivatives and ring opening
reactions to R,â-diamino esters and a γ-amino R,â-unsaturated amino ester.
Introduction
relevant compounds and precursors of 3-amino-â-lactams,3 have
received far less attention.
The incorporation of conformationally constrained R-amino
acids1 and, more recently, â-amino acids2 into biologically active
peptides has gained great interest in the preparation of peptide-
based drug molecules. R,â-Diamino acids 1, as biological
2-Aziridinylglycines 2 and derivatives thereof, such as esters
and amides, can be considered as a virtually new class of
conformationally constrained heterocyclic R,â-diamino acid
derivatives of which only few representatives have been
described. Recently, the synthesis of a N-Cbz-protected 2-aziri-
dinylglycinamide 3 was reported in low yield via rearrangement
of 3-{[(benzyloxy)carbonyl]amino}-4-(mesyloxymethyl)-1-(4-
methoxyphenyl)-2-azetidinone upon treatment with ammonia,4
analogous to the transformation of 4-(1-haloalkyl)-2-azetidinones
with sodium methoxide in methanol to methyl 4-(alkylamino)-
pentenoates via intermediate methyl 2-aziridinylacetates.5 The
† Ghent University.
| University of Szeged.
¶ University of Jyva¨skyla¨.
‡ On leave from University of Szeged.
§ Postdoctoral Fellow of the Research Foundation-Flanders (FWO).
(1) (a) Cowell, S. M.; Lee, Y. S.; Cain, J. P.; Hruby, V. J. Curr. Med.
Chem. 2004, 11, 2785. (b) Komarov, I. V.; Grigorenko, A. O.; Turov, A.
V.; Khilya, V. P. Russ. Chem. ReV. 2004, 73, 785. (c) Park, K. H.; Kurth,
M. J. Tetrahedron 2002, 58, 8629.
10.1021/jo0710634 CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/17/2007
J. Org. Chem. 2007, 72, 7199-7206
7199

Kiss et al.
SCHEME 1. Retrosynthetic Analysis of the â,γ-Aziridino
Swern oxidation of a 2-[1-(dibenzyl)amino-2-hydroxyethyl]-
aziridine resulted in unstable R-(N,N-dibenzyl)amino-2-aziridine-
acetaldehyde 4,6 while hydrazone 5 was prepared from the
corresponding N-methoxy-2-methoxyoxalyl-3,3-(dimethoxy-
carbonyl)aziridine.7 Strecker reaction of aziridine-2-carbox-
aldimines with trimethylsilyl cyanide stereoselectively afforded
R-amino 2-aziridinylacetonitriles 6, which could be used in
further ring opening reactions.8 2-Aziridinylglycines 2 are
potentially very interesting compounds from biological as well
as from synthetic point of view. Besides their application as
conformationally restricted analogues of physiologically active
R,â-diamino acids and peptides, they are also related to
2-(aziridin-2-yl)-3-phenylpropionic acid 7 which is a carboxy-
peptidase A inhibitor.9 Aziridines are of great importance as
structural components of natural and biologically active prod-
ucts.10 For instance, azinomycines A and B and mitomycin C
are potent antitumor and antibiotic agents.11a Aziridines are also
important heterocyclic compounds in the synthesis of a variety
of nitrogen-containing compounds such as amino sugars,
alkaloids, and substituted amino acids.11 Considerable efforts
have been made to nucleophilic ring opening of aziridines.12
2-Aziridinylglycines 2, being substituted 2-aziridinylacetates13
which in their turn are the homologues of aziridine-2-carbox-
ylates,14 could be useful building blocks for the synthesis of
functionalized R,â- and R,γ-diamino acid derivatives.
r-Amino Esters 8
Results and Discussion
According to the retrosynthetic analysis of the target com-
pounds 8, the readily available benzophenone imine glycine
esters 10 and N-(p-toluenesulfonyl) R-chloroimine derivatives
9 seemed to be suitable starting materials for this goal (Scheme
1).
A convenient method for the stereoselective synthesis of R,â-
diamino acid derivatives involves Mannich reaction of R-amino
ester derivatives across imines.15 This methodology has also
been applied in the synthesis of 3-amino-â-lactams via cycliza-
tion of intermediate R,â-diamino esters.16 Despite the numerous
approaches to â-amino esters,17 â-trifluoromethyl-â-amino
esters,18 R-oxy-â-amino esters,19 γ-alkoxy-â-amino esters,20 R,R-
difluoro-â-amino esters,21 R-cyano-â-amino esters,22 â-amino
diesters,23 aspartic acid derivatives,24 â′-keto-â-amino esters,25
aziridine-2-carboxylic esters,26 C-glycosyl â-amino esters,27 and
R,â-diamino acid derivatives of biological importance by
Mannich condensation of ester enolates or equivalents with
imines recently reported, only two isolated examples have been
published in which a chloro substituent is present at the
R-position of the CdN double bond of the reacting imine in
broad sense, that is, hydrazones and in situ formed imines
included.28,29 More specifically, it concerned here chloroacet-
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Our present aim was to develop a method for the synthesis
of conformationally constrained aziridino amino ester diaster-
eomers 8 bearing the nitrogen moieties in R,â,γ-positions of
the ester, filling up part of the gap of the chemistry of R-amino
2-aziridinylacetate derivatives.
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7200 J. Org. Chem., Vol. 72, No. 19, 2007

Access to â,γ-Aziridino R-Amino Ester DeriVatiVes
SCHEME 2. Synthesis of r-Chloroaldimines 9
aldehyde derivatives which are not general in view of their
lability. The condensation of ester enolates with R-chloroimines
would lead to â-amino-γ-chloro esters as suitable intermediates
for further cyclization to 2-aziridinylacetates. An acylhydrazone
derived from chloroacetaldehyde reacted via a zirconium-
catalyzed asymmetric Mannich-type reaction with the silyl enol
ether derived from methyl isobutyrate to afford the correspond-
ing â-N′-acylhydrazino-γ-chlorocarboxylic ester adduct.28 Simi-
larly, HBF4-catalyzed three-component coupling reaction of
chloroacetaldehyde, aniline, and the silyl enol ether derived from
methyl isobutyrate took place smoothly in water in the presence
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of a surfactant.29 However, in neither of the latter two reports
the â-amino-γ-chloro esters were further investigated.
The aliphatic aldehydes 11a-c were first transformed to their
corresponding N-(p-toluenesulfonyl) aldimines 12a-c according
to a known literature procedure involving the reaction of
aldehydes 11 with p-toluenesulfonamide and sodium p-toluene-
sulfinate in aqueous formic acid and subsequent treatment with
sodium bicarbonate.30 The aliphatic aldimines 12 were then
submitted to R-chlorination with N-chlorosuccinimide (NCS),
furnishing the desired new R-chloroimines 9a-c in 91-96%
yield (Scheme 2). These new non-enolizable activated R-chloro-
aldimines 9 were obtained exclusively as the E-isomers in
acceptable purity after removal of the formed succinimide by
simple filtration or extractive workup. All attempts to obtain
analytically pure samples of the R-chloroaldimines 9 via
recrystallization failed, however, due to their instability upon
storage in solution, even at low temperature, and it proved
necessary to immediately use the aldimines 9 as such in the
next step.
The nucleophilic attack of the benzophenone imine glycine
esters 10 across the N-(p-toluenesulfonyl) R-chloroaldimines 9
was studied under different base conditions with ethyl ester 10a
and the aldimine 9a derived from isobutyraldehyde (11a) as
model compounds.31 In the presence of KOtBu in THF or under
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J. Org. Chem, Vol. 72, No. 19, 2007 7201

Kiss et al.
SCHEME 3. Synthesis of Diamino Esters 13 and 14 from
N-Tosyl Aldimines 9 and Benzophenone Imine Glycinates 10
amino carboxylic esters in literature allows a preliminary
stereochemical determination.15k For analogous â-aryl-R-(di-
phenylmethylene)amino-â-(p-toluenesulfonyl)amino carboxylic
esters, the Hâ hydrogen of the syn isomer appears at higher
chemical shift as compared to the anti isomer. Additionally,
the vicinal coupling constant 3JHR-Hâ for the syn isomer shows
a smaller value than the anti isomer. These chemical correlations
are in agreement with the minor isomers 14 obtained by us,
and the relative stereochemistry of the minor isomers 14 was
thus tentatively assigned as being syn. Moreover, the vicinal
3
coupling constant JHR-Hâ for the syn isomers 14ab (3JHR-Hâ
) 1.1 Hz) and 14bb (3JHR-Hâ ) 0.83 Hz) has a comparable
3
small value as the observed vicinal coupling constant JHR-Hâ
of the closely related nonchlorinated â-isopropyl- (3JHR-Hâ
)
1.6 Hz) and â-cyclohexyl-R-(diphenylmethylene)amino-â-(p-
toluenesulfonyl)amino carboxylic esters (3JHR-Hâ ) 1.2 Hz).15k
Adducts 13aa,ab,ac,ba and 14aa,ab,ba could be isolated as
single diastereomers by crystallization from mixtures of hexane/
EtOAc in good yields. The minor syn isomers 14aa,ab,ba
crystallized first from the reaction mixtures and the major anti
isomers 13aa,ab,ba could be subsequently recovered as solid
compounds almost quantitatively from the filtrate by concentra-
tion. Only anti isomer 13ac crystallized from the 1:1 mixture
13ac/14ac which made it impossible to isolate the syn isomer
14ac as a stereochemically pure compound. All attempts to
separate diastereomers 13bb/14bb and 13ca/14ca via selective
crystallization failed, and therefore these mixtures were used
as such in the subsequent ring closing step, after which
separation of the diastereomers would be attempted again (vide
infra).
The anti stereoselectivity of the Mannich addition reaction
of the glycine enolates 15 with the N-tosylimines 9 can be
explained on the basis of the conformational arrangement in
the proposed transition state of the reaction (Figure 1). Due to
intramolecular chelation, the enolates 15 are expected to have
the Z-geometry.15h,32 When considering a cyclic chelated six-
membered chairlike transition state, such as the Zimmerman-
Traxler model,33 in aldol reactions, one can apply as a rule of
thumb that (Z)-enolates result in syn-aldol products. However,
in Mannich reactions, the E-geometry of the electrophilic
aldimines, such as N-tosylimines 9, restricts the latter compounds
to only one binding conformation in the Zimmerman-Traxler
model,34 which results in the formation of anti-Mannich adducts
from (Z)-enolates. Therefore, the obtained anti stereoselectivity
in adducts 13 is in accordance with the chairlike transition state
model TS-1, in analogy to a model proposed by Davis.15h
Despite the disfavoring 1,3-diaxial interaction between the
haloalkyl group (CClR2) and the alkoxy function (OR′), which
explains the better anti diastereoselectivity with smaller R′
groups, TS-1 is likely to be favored due to the coordinating
ability of the chlorine atom and, to a lesser extent, one of the
oxygen atoms on sulfur with lithium.35 However, a less sterically
congested open transition state TS-2 cannot be excluded to
explain the formation of the anti adducts 13. The formation of
TABLE 1. Addition of Glycinates 10 to Aldimines 9a
entry
9
10
dr (13:14)b (yield)
13 (%)c
14 (%)c
1
2
3
4
5
6
9a
9a
9a
9b
9b
9c
10a
10b
10c
10a
10b
10a
13aa/14aa ) 2:1 (66%)
13ab/14ab ) 2.5:1 (57%)
13ac/14ac ) 1:1 (48%)
13ba/14ba ) 2:1 (83%)
13bb/14bb ) 3.5:1 (68%)
13ca/14ca ) 2:1 (80%)
43
40
24
46
22
17
22
a All reactions were performed at -78 °C in THF for 2 h using 1 equiv
of 9, 1 equiv of 10, and 1 equiv of LDA. b Determined by 1H NMR analysis
(300 MHz) of the crude reaction mixtures. c Isolated yield of pure
diastereomers after crystallization.
phase transfer conditions (NaOH, benzyltriethylammonium
chloride, toluene/water), the reaction failed to give the desired
1,2-adducts. In the presence of LiClO4 and Et3N in THF,15k the
two possible anti and syn diastereomers 13aa and 14aa
unfortunately were formed only in low yield in 2:1 ratio together
with unreacted starting material. However, when the reaction
of ethyl glycinate 10a with N-tosylimine 9a was effected by
initial deprotonation of the ester with lithium diisopropylamide
(LDA) in THF at -78 °C, a mixture of syn and anti diastere-
omers 13aa and 14aa was formed in good yield with moderate
diastereoselectivity (dr 2:1) (Scheme 3 and Table 1, entry 1).
Under the latter reaction conditions, the addition to the N-
tosylimine 9a was also accomplished in acceptable yield by
using the methyl and tert-butyl glycine esters 10b and 10c (Table
1, entries 2 and 3). The sterical bulk of the ester 10 had moderate
influence on the diastereoselectivity of the reaction with the
anti/syn ratio decreasing from 2.5:1 to 1:1 in the order Me:Et:
t-Bu. The scope of the nucleophilic addition of glycine ethyl
ester 10a was extended to the larger alkyl-substituted R-chloro-
imines 9b (R-R ) Cy) and 9c (R ) Et) (Table 1, entries 4
and 6). In both cases, the ratio of the anti 13ba,ca and syn
14ba,ca Mannich adduct was determined to be 2:1, demonstrat-
ing that the sterical bulk of the aldimine 9 had little influence
on the diastereoselectivity of the Mannich reaction. However,
a higher anti diastereoselectivity was observed again when the
methyl ester adducts 13bb/14bb were synthesized (Table 1,
entry 5). Determination of the diastereomeric ratios was based
on the relative integration values of the distinguishable â-hy-
drogens of the anti and syn adducts 13 and 14 in the crude
reaction mixtures. The chemical shifts or the values of coupling
constants of acyclic R-(diphenylmethylene)amino-â-(p-toluene-
sulfonyl)amino carboxylic esters 13/14 cannot be used for an
unambiguous determination of their relative stereochemistry.
However, comparison with closely related stereochemically
defined R-(diphenylmethylene)amino-â-(p-toluenesulfonyl)-
(32) Ezquerra, J.; Pedregal, C.; Merino, I.; Florez, J.; Barluenga, J.;
Garcia-Granda, S.; Llorca, M. A. J. Org. Chem. 1999, 64, 6554.
(33) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79,
1920.
(34) Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem. 1982,
13, 1.
(35) For the stereochemical explanation of Grignard additions to
R-chloro-tert-butanesulfinyl aldimines via the coordinating ability of the
R-chloro atom with magnesium, see: Denolf, B.; Mangelinckx, S.; To¨rnroos,
K. W.; De Kimpe, N. Org. Lett. 2006, 8, 3129.
7202 J. Org. Chem., Vol. 72, No. 19, 2007

Access to â,γ-Aziridino R-Amino Ester DeriVatiVes
FIGURE 1. Possible transition states in the formation of the anti and syn diastereomers 13 and 14.
SCHEME 4. Formation and Isomerization Reaction of the
anti Adduct 13ab
the retro-Mannich fragmentation of the initially formed lithiated
anti adduct 16. Via the retro-Mannich fragmentation, the
formation of imine 9 with Z-stereochemistry, as present in
transition state TS-4, is possible.37 Very recently, the group of
Davis also described that the kinetically favored anti-2,3-
diamino ester, resulting from the addition of benzophenone
imine glycinate 10a across (S)-(+)-N-(benzylidene)-p-toluene-
sulfinamide, isomerized via retro-Mannich fragmentation to the
more stable syn-2,3-diamino ester under thermodynamic reaction
conditions.15y In further analogy with suggestions of the group
of Davis, it is believed that lithiated syn adduct 17 is
thermodynamically favored due to the occurrence of an equi-
librium with the intramolecular chelated complex 18 which is
sterically favored due to the trans configuration of the five-
membered complex.15y
TABLE 2. Formation and Isomerization Reaction of the anti
Adduct 13ab (Scheme 4)
Furthermore, an isomerization of the isolated anti isomer 13ab
into the thermodynamically more stable syn isomer 14ab and
syn-aziridine 20ab was observed upon stirring under mild base
conditions (iPr2NH, LiCl, rt) (Scheme 5 and Table 3).
yieldb yieldb recoveryb
reaction
entry time (h) 13ab:14ab
ratioa
13ab 14ab
10b
ratioa
14ab:20ab
(%)
(%)
(%)
1
2
3
1
2
20
9:1
2.5:1
37
40
0
24
10
Having partially solved the separation of the two diastereo-
mers 13 and 14 by crystallization from a hexane/ethyl acetate
mixture, the aziridine ring at the â,γ-position was constructed
by intramolecular 1,3-displacement of the chloride under basic
condition. The reaction of the pure diastereomers 13aa,ab,ac,ba
and 14aa,ab,ba was performed easily with K2CO3 in refluxing
acetone for 5 h giving the â,γ-aziridino-R-(N-diphenylmeth-
ylidene)amino esters 19aa,ab,ac,ba and 20aa,ab,ba in 58-87%
yield (Scheme 6). As presented above, the complete separation
of adducts 13ca and 14ca proved impossible. Noteworthy, the
aziridine formation from the mixture of adducts 13ca/14ca gave
a mixture of diethyl-substituted aziridines 19ca/20ca which
17
1:1
a Determined by 1H NMR analysis (300 MHz) of the crude reaction
mixtures. b Isolated yields of pure compounds.
the syn adducts 14, especially in the derivatives with the larger
R′ groups, can be explained via a boatlike transition state TS-3
involving the (E)-N-tosylimines 9.36
In order to get some better insight in the mechanism of the
Mannich addition, the reaction of benzophenone imine glycine
10b and the R-chloroimine 9a was performed under thermo-
dynamic control (Scheme 4 and Table 2), that is, extended
reaction time (20 h) at room temperature. The fact that the syn
isomer 14ab, together with the syn-aziridine 20ab (vide infra),
instead of the kinetically favored anti adduct 13ab, was formed
upon stirring for 20 h gives support for an alternative six-
membered chelate chairlike transition state TS-4, resulting from
(36) For similar discussions on chair- and boatlike transition states in
addition reactions of enolates to imines, see ref 17c and: Bernardi, A.;
Gennari, C.; Raimondi, L.; Villa, M. B. Tetrahedron 1997, 53, 7705.
(37) Corey, E. J.; Decicco, C. P.; Newbold, R. C. Tetrahedron Lett. 1991,
32, 5287.
J. Org. Chem, Vol. 72, No. 19, 2007 7203

Kiss et al.
SCHEME 5. Isomerization Reaction of the anti Adduct
13ab
SCHEME 7. Synthesis of the Aziridino Amino Esters 19ca
and 20ca
SCHEME 8. Base-Induced Formation of
4-Aminopentenoate 21 from anti- or syn-Aziridines 19aa and
20aa
TABLE 3. Isomerization Reaction of the anti Adduct 13ab upon
Treatment with LiCl/iPr2NH in THF at rt (Scheme 5)
entry
reaction time
ratio 13ab:14ab:20aba
1
2
3
4
15 h
35 h
3 days
5 days
2:1:0
1:1.2:traces
1:2:2
1:5:5
a Determined by 1H NMR analysis (300 MHz) of the crude reaction
mixtures.
SCHEME 6. Synthesis of the Aziridino Amino Esters
19aa,ab,ac,ba and 20aa,ab,ba
In the presence of a stronger base (KOtBu), both the anti-
and syn-aziridine derivatives 19aa and 20aa resulted in the same
γ-amino R,â-unsaturated amino ester 21 formed by deprotona-
tion in the R-position of the ester and double bond formation
by expulsion of the aziridine nitrogen (1,2-elimination) (Scheme
8). The latter mechanism is analogous to our previously reported
mechanism in the synthesis of methyl 2-alkoxy-4-(alkylamino)-
pentenoates from intermediate methyl 2-aziridinylacetates.5
When the ring opening with KOtBu in THF was performed on
the syn-aziridine 20aa, trans-lactone 22 could be isolated in
38% yield from the reaction mixture as a side product besides
allylamine 21. The determination of the trans stereochemistry
of lactone 22 is based on observed NOE effects (Figure 2) and
supported by the relative large vicinal coupling constant 3JHR-Hâ
(J ) 9.63 Hz).38 The 4-aminopentenoate 21 is assumed to
possess the Z-geometry according to the reaction mechanism
via anti elimination (Scheme 9). The assumption is made that
the anti-aziridine 19aa again isomerizes to the syn-aziridine 20aa
under the reaction conditions which subsequently led to the
formation of the corresponding (Z)-pentenoate 21. The assump-
tion for the Z-geometry is supported by the appearance of the
olefinic â-proton at 5.90 ppm in the 1H NMR spectrum (CDCl3,
300 MHz). The latter chemical shift is near to the range of 6.18-
6.25 ppm in which the olefinic protons appeared of the
analogous (Z)-methyl 2-alkoxy-4-(alkylamino)pentenoates, while
the chemical shift of the olefinic proton of (E)-methyl 2-alkoxy-
4-(alkylamino)pentenoates was higher (i.e., 6.55-6.60 ppm).5
could be separated by crystallization from a hexane/EtOAc
solvent system in good yield (Scheme 7). The vicinal coupling
constant 3JHR-Hâ for the anti isomers 19 shows a smaller value
(J ) 8.53-8.81 Hz) than the syn isomers 20 (J ) 9.08-9.36
Hz). The structure and the stereochemical arrangement of the
aziridino derivatives 19aa, 19ab, 19ac, 19ca, and 20aa were
unambigously determined by their X-ray diffraction analysis
(see presented ORTEP figures in the Supporting Information),
which also confirms the anti and syn assignments of adducts
13 and 14.
It was interesting to observe that when the cyclization reaction
from the anti adduct 13aa was continued for a longer time (16
h) a mixture of aziridines 19aa/20aa was detected in 5:1 ratio.
It was found that, in analogy with the isomerization of 13ab to
14ab, the anti-aziridine 19aa could be isomerized under mild
base conditions (iPr2NH, LiCl, THF, rt) to the syn isomer 20aa
in 97% yield (Scheme 6).
FIGURE 2. Determination of trans stereochemistry of lactone 22 via
a 2D NOESY experiment.
7204 J. Org. Chem., Vol. 72, No. 19, 2007

Access to â,γ-Aziridino R-Amino Ester DeriVatiVes
SCHEME 9. Mechanism for the Formation of
SCHEME 11. Formation of the N-Boc-Protected Aziridino
(Z)-Pentenoate 21
Amino Esters 26
6H, J ) 7.43 Hz), 1.59 (dq, 4H, J ) 7.15 Hz, J ) 7.43 Hz), 2.32
(sextet, 1H, J ) 6.60 Hz), 2.43 (s, 3H), 7.33 (d, 2H, J ) 7.98 Hz),
7.81 (d, 2H, J ) 8.26 Hz), 8.44 (d, 1H, J ) 6.33 Hz); 13C NMR
(75 MHz, CDCl3) δ ) 11.4, 21.6, 24.0, 48.2, 128.0, 129.8, 135.0,
144.6, 181.8; IR (NaCl, cm-1) ν ) 1626, 1598, 1459, 1325, 1160,
1091, 815, 758, 672; MS (ES, pos) m/z 254 (M + H+, 100).
General Procedure for the Preparation of R-Chloroimines
9. To a solution of N-(p-toluenesulfonyl)imine 12 (40 mmol) in
CCl4 (50 mL) was added N-chlorosuccinimide (1 equiv) in portions
after which the mixture was stirred at reflux for 18 h. After cooling
of the reaction mixture, the solid was filtered off and the filtrate
was concentrated in vacuo giving the N-tosyl R-chloroimine 9
(purity >70%) which was used immediately in the next step without
purification (if purity was >80%). Alternatively, this imine was
taken up in CCl4 (100 mL), rapidly washed with 0.5 N aq NaOH
(1 × 50 mL) and ice-water (3 × 70 mL), dried (MgSO4), and
concentrated under reduced pressure to give the N-tosyl R-chloro-
imines 9 which were spectroscopically analyzed (purity ∼ 80-
90%).
SCHEME 10. Formation of the N-Boc-Protected Aziridino
Amino Esters 25
N-(2-Chloro-2-methylpropylidene)-p-toluenesulfonamide (9a).
White solid; mp 88-89 °C; yield 96%; 1H NMR (300 MHz, CDCl3)
δ ) 1.72 (s, 6H), 2.44 (s, 3H), 7.36 (d, 2H, J ) 7.98 Hz), 7.81 (d,
2H, J ) 8.26 Hz), 8.45 (s, 1H); 13C NMR (75 MHz, CDCl3) δ )
Analogous γ-amino R,â-unsaturated amino esters have proven
to be useful synthetic intermediates for Diels-Alder and 1,3-
dipolar cycloaddition reactions39 for the synthesis of chiral R,γ-
diamino acid derivatives,40 as dipeptidyl peptidase inhibitors,41
and for the synthesis of functionalized pyrrolin-2-ones.42
To further demonstrate the synthetic potential of the aziridines
19 and 20, the deprotection and reprotection of the R-amino-
function was investigated. The anti-aziridino ester 19aa could
be converted easily into the corresponding N-Boc-protected
derivative 25 by hydrolysis with aqueous HCl followed by
protection with Boc2O (Scheme 10). During the acidic hydroly-
sis of 19aa and, especially, of 20aa, the three-membered ring
was opened by chloride resulting in anti- and syn-γ-chloro-
R,â-diamino esters 23 and 24. From the syn compound 24, the
N-Boc-protected aziridine 26 was formed by treatment with
K2CO3 (Scheme 11).
In conclusion, an efficient synthesis of â,γ-aziridino R-amino
ester diastereomers has been achieved based on Mannich
addition of glycinates across R-chlorinated aldimines and
subsequent intramolecular ring closure. The stereochemically
pure and synthetically useful anti- and syn-aziridines were
obtained via selective crystallizations. These strained diamino
acid derivatives are expected to react via regioselective opening
of their aziridine ring, which would allow further stereoselective
functionalizations of the corresponding R-amino acid derivatives.
21.8, 28.3, 66.3, 128.3, 130.1, 133.7, 145.4, 174.5; IR (KBr, cm-1
)
ν ) 3250, 2924, 1704, 1598, 1375, 1159, 1055; MS (ES, pos) m/z
260/262 (M + H+, 80). Due to the lability of this compound, no
acceptable elemental analysis could be obtained.
General Procedure for the Addition Reaction of Benzophe-
none Imine Glycine Esters 10 to R-Chloro N-Tosylimines 9. To
a solution of LDA (15 mmol) in dry THF (10 mL) was added
benzophenone imine glycine ester 10 (15 mmol) in dry THF (25
mL) at -78 °C and stirred for 15 min. Then a solution of N-tosyl
R-chloroimine 9 (15 mmol) in dry THF (30 mL) was added
dropwise, and the mixture was stirred at -78 °C. After 2 h, a
solution of saturated NH4Cl (25 mL) was added to the reaction
mixture and extracted with EtOAc (3 × 80 mL). The organic layer
was dried (MgSO4) and concentrated under reduced pressure. The
diastereomers 13aa,ab,ac,ba and 14aa,ab,ba were isolated after
crystallization of the crude mixture from hexane/EtOAc by which
the minor isomers 14aa,ab,ba and the isomer 13ac crystallized first
and the major isomers 13aa,ab,ba were obtained by crystallization
from the filtrate. Adducts 13bb,ca and 14bb,ca were isolated as
mixtures of diastereomers.
(38) Jaime, C.; Segura, C.; Dinare´s, I.; Font, J. J. Org. Chem. 1993, 58,
154.
(39) Reetz, M. T.; Kayser, F.; Harms, K. Tetrahedron Lett. 1992, 33,
3453.
(40) Reetz, M. T.; Kayser, F. Tetrahedron: Asymmetry 1992, 3, 1377.
(41) Soroka, A.; Van der Veken, P.; De Meester, I.; Lambeir, A.-M.;
Maes, M.-B.; Scharpe´, S.; Haemers, A.; Augustyns, K. Bioorg. Med. Chem.
Lett. 2006, 16, 4777.
(42) (a) Inguimbert, N.; Dhoˆtel, H.; Coric, P.; Roques, B. P. Tetrahedron
Lett. 2005, 46, 3517. (b) Wu, Y. C.; Liu, L.; Wang, D.; Chen, Y. J. J.
Heterocycl. Chem. 2006, 43, 949.
Experimental Section
Imines 12 were prepared according to a literature procedure.30
N-(2-Ethylbutylidene)-p-toluenesulfonamide (12c): Light yel-
1
lowish oil; yield 54%; H NMR (300 MHz, CDCl3) δ ) 0.85 (t,
J. Org. Chem, Vol. 72, No. 19, 2007 7205

Kiss et al.
anti-Ethyl 4-Chloro-2-(diphenylmethylenamino)-4-methyl-3-
(p-toluenesulfonylamido)pentanoate (13aa). Yellow solid; mp
114-116 °C; yield 43% (after crystallization); 1H NMR (300 MHz,
CDCl3) δ ) 1.19 (t, 3H, J ) 7.15 Hz), 1.46 (s, 3H), 1.49 (s, 3H),
2.37 (s, 3H), 3.88 (dd, 1H, J ) 3.03 Hz, J ) 9.08 Hz), 4.04 (q,
2H, J ) 7.15 Hz), 4.57 (d, 1H, J ) 3.03 Hz), 6.33 (d, 1H, J )
9.08 Hz), 7.11-7.49 (m, 12H), 7.76-7.81 (m, 2H); 13C NMR (75
MHz, CDCl3) δ ) 13.8, 21.6, 30.6, 30.8, 61.4, 64.8, 65.5, 71.9,
126.9, 127.5, 127.9, 128.6, 128.8, 129.1, 129.4, 130.6, 135.8, 138.8,
139.0, 142.7, 171.1, 172.3; IR (KBr, cm-1) ν ) 3327, 2975, 1743,
1627, 1446, 1322, 1088; MS (ES, pos) m/z 527/529 (M + H+,
100). Anal. Calcd for C28H31ClN2O4S: C, 63.80; H, 5.93; N, 5.31;
S, 6.08. Found: C, 63.67; H, 5.89; N, 5.23; S, 6.01.
General Procedure for the Formation of â,γ-Aziridino
R-Amino Esters 19 and 20. A solution of R,â-diamino ester 13 or
14 (3 mmol) in acetone (30 mL) was treated with K2CO3 (3 equiv),
and the mixture was stirred at reflux for 5 h. After cooling of the
reaction mixture, the solid was filtered off and the filtrate was
concentrated in vacuo. The residue was taken up in EtOAc (100
mL) and washed with H2O (3 × 60 mL). The organic layer was
dried (MgSO4) and then concentrated under reduced pressure. The
crude product was purified by crystallization from hexane/EtOAc.
anti-Ethyl 2-(3,3-Dimethyl-1-tosylaziridin-2-yl)-2-(diphenyl-
methyleneamino)acetate (19aa). White crystals; mp 147-148 °C;
yield 82%; 1H NMR (300 MHz, CDCl3) δ ) 1.03 (s, 3H), 1.10 (t,
3H, J ) 7.15 Hz), 1.73 (s, 3H), 2.40 (s, 3H), 3.71 (d, 1H, J ) 8.53
Hz), 3.74-3.93 (m, 2H), 3.84 (d, 1H, J ) 8.53 Hz), 7.10-7.83
(m, 14H); 13C NMR (75 MHz, CDCl3) δ ) 14.0, 21.5, 21.61, 21.64,
50.2, 53.1, 61.4, 65.2, 127.8, 128.1, 128.2, 128.6, 129.1, 129.2,
129.3, 130.9, 135.7, 138.2, 139.3, 143.7, 169.9, 171.9; IR (KBr,
cm-1) ν ) 3443, 2981, 2937, 1733, 1615, 1322, 1186, 1157, 1086.
MS (ES, pos) m/z 491 (M + H+, 100). Anal. Calcd for
C28H30N2O4S: C, 68.55; H, 6.16; N, 5.71; S, 6.54. Found: C, 68.42;
H, 6.28; N, 5.61; S, 6.50.
General Procedure for the Isomerization of Adduct 13ab and
Aziridine 19aa. Adduct 13ab or aziridine 19aa (0.4 mmol) was
dissolved in 10 mL of THF. To this solution were added 17 mg (1
equiv) of LiCl and 40 mg (1 equiv) of diisopropylamine, and the
mixture was stirred at room temperature for the period of time as
mentioned in the Discussion. Water (15 mL) was added to this
mixture, and the reaction mixture was extracted with EtOAc (20
mL), dried (MgSO4), and concentrated under reduced pressure.
Ethyl 2-(Diphenylmethyleneamino)-4-methyl-4-(p-toluene-
sulfonylamido)pent-2-enoate (21). To a solution of aziridine 19aa
or 20aa (1.33 mmol) in 15 mL of dry THF was added in portions
1.33 mmol of KOtBu. After stirring the mixture for 4 h at room
temperature, water (25 mL) was added and extraction was
performed with EtOAc (3 × 25 mL). The organic layer was dried
(MgSO4) and concentrated in vacuo. Column chromatography on
silica gel (hexanes/EtOAc 2:1) afforded allylamine 21 and lactone
22 when starting from aziridine 20aa: Yellow oil; yield 60% from
19aa; 55% from 20aa (column chromatography on silica gel:
hexanes/EtOAc 2:1); Rf ) 0.36; 1H NMR (300 MHz, CDCl3) δ )
0.93 (t, 3H, J ) 7.15 Hz), 1.48 (s, 6H), 2.31 (s, 3H), 3.65 (q, 2H,
J ) 7.15 Hz), 5.90 (s, 1H), 7.06 (d, 2H, J ) 7.98 Hz), 7.21-7.57
(m, 8H), 7.61 (d, 2H, J ) 8.26 Hz), 7.75-7.78 (m, 2H), 7.82 (s,
1H); 13C NMR (75 MHz, CDCl3) δ ) 13.9, 21.5, 28.9, 56.1, 60.9,
127.2, 128.2, 128.6, 129.1, 129.4, 130.0, 130.1, 131.8, 133.9, 136.7,
138.2, 138.7, 140.1, 142.5, 163.4, 170.6; IR (NaCl, cm-1) ν ) 3369,
2927, 2971, 1720, 1598, 1321, 1157, 1093; MS (ES, pos) m/z 491
(M + H+, 100).
anti-Ethyl 2-(tert-Butoxycarbonylamino)-2-(3,3-dimethyl-1-
tosylaziridin-2-yl)acetate (25). A solution of aziridine 19aa (1.43
mmol) and 18% aq HCl (0.5 mL) in THF (20 mL) was stirred for
1 h. Then a saturated solution of NaHCO3 in H2O (40 mL) was
added. The mixture was extracted with EtOAc (3 × 25 mL), dried
(MgSO4), and concentrated in vacuo. To the crude product in THF
(25 mL) were added Et3N (2.9 mmol) and Boc2O (1.5 mmol), and
the mixture was stirred for 6 h. Then it was taken up in EtOAc (60
mL), washed with H2O, dried (MgSO4), and concentrated in vacuo.
The residue was purified by chromatography over silica gel (hexane/
EtOAc 4:1) affording aziridine 25 and diaminoester 23: White
crystals; mp 96-99 °C; yield 68%; Rf ) 0.14; 1H NMR (300 MHz,
CDCl3) δ ) 1.01 (t, 3H, J ) 6.88 Hz), 1.42 (s, 12H), 1.73 (s, 3H),
2.42 (s, 3H), 3.06 (d, 1H, J ) 8.81 Hz), 3.48-3.53 (m, 1H), 3.90
(dq, 1H, J ) 7.15 Hz, J ) 10.46 Hz), 4.01-4.07 (m, 1H), 5.27 (br
d, 1H, J ) 7.98 Hz), 7.31 (d, 2H, J ) 7.98 Hz), 7.81 (d, 2H, J )
8.26 Hz); 13C NMR (75 MHz, CDCl3) δ ) 13.9, 21.2, 21.6, 21.8,
28.3, 51.2, 51.9, 52.2, 61.6, 80.4, 127.8, 129.4, 138.0, 143.9, 154.6,
170.4; IR (KBr, cm-1) ν ) 3247, 3132, 2977, 1750, 1705, 1324,
1162; MS (ES, pos) m/z 449 (M + Na+, 8), 371 (100), 327 (58),
200 (36). Anal. Calcd for C20H30N2O6S: C, 56.32; H, 7.09; N, 6.57;
S, 7.52. Found: C, 55.93; H, 6.84; N, 6.60; S, 8.01.
X-ray Crystallographic Study: Crystallographic data were
collected at 173 K with a Nonius-Kappa CCD area detector
diffractometer using graphite-monochromatized Mo KR radiation
(λ ) 0.71073 Å) as reported earlier.43 The structures were solved
by direct methods using of the SHELXS-97 program,44 and full-
matrix, least-squares refinements on F2 were performed by using
the SHELXL-97 program.44 The CH hydrogen atoms were included
at the fixed distances with the fixed displacement parameters from
their host atoms. The deposition number CCDC 636457-636461
contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge at ww.ccdc.cam.ac.uk/
conts/retrieving.html [or from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: (int.) +
44-1223-336-033; e-mail deposit@ccdc.cam.ac.uk].
Acknowledgment. The authors are indebted to Ghent
University (BOF, Bilateral Scientific Cooperation Programme
Flanders-Hungary) and the “Fund for Scientific Research-
Flanders (Belgium)” (FWO-Vlaanderen) for financial support
of this research.
Supporting Information Available: General information,
spectroscopic data for compounds 9b, 9c, 13ab-ca, 14aa-ca,
19ab-ca, 20aa,ab,ba,ca, 22, and 23, experimental procedures
and spectroscopic data for compounds 24 and 26, and X-ray
diffraction analysis of compounds 19aa, 20aa, 19ab, 19ac, and
19ca. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO0710634
(43) Kanizsai, I.; Szakonyi, Z.; Sillanpa¨a¨, R.; D’hooghe, M.; De Kimpe,
N.; Fu¨lo¨p, F. Tetrahedron: Asymmetry 2006, 17, 2857.
(44) Sheldrick, G. M. SHELX-97, Program for the solution and refinement
of crystal structures; University of Go¨ttingen: Go¨ttingen, Germany, 1997.
7206 J. Org. Chem., Vol. 72, No. 19, 2007