Enantioselective synthesis of aziridine 2,2-dicarboxylates. Part II: Determination of the absolute configuration

Article abstract of DOI:10.1016/S0957-4166(02)00341-5

The absolute configuration of aziridine-2,2-dicarboxylates was determined through their transformation into the corresponding diastereomeric (S)-(-)-α-methylbenzylamido derivatives. The data obtained allows establishment of the stereochemistry of the firs

Full text of DOI:10.1016/S0957-4166(02)00341-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1411–1415
Enantioselective synthesis of aziridine 2,2-dicarboxylates.
Part 2: Determination of the absolute configuration
Giuliana Cardillo,* Serena Fabbroni, Luca Gentilucci, Massimo Gianotti, Rossana Perciaccante,
Simona Selva and Alessandra Tolomelli
Dipartimento di Chimica ‘G. Ciamician’, Universita` di Bologna, Via Selmi 2, 40126, Bologna, Italy
Received 17 June 2002; accepted 28 June 2002
Abstract—The absolute configuration of aziridine-2,2-dicarboxylates was determined through their transformation into the
corresponding diastereomeric (S)-(−)-a-methylbenzylamido derivatives. The data obtained allows establishment of the stereochem-
istry of the first step of the conjugate addition reaction catalyzed by chiral bisoxazoline–Cu complex. © 2002 Elsevier Science Ltd.
All rights reserved.
1. Introduction
basic conditions. The conjugate addition performed in
CH2Cl2 at −10°C gives the adduct 2 in 50–80% yield
with enantioselectivity that strongly depends upon the
alkyl substituent attached to the double bond. In all
cases, cyclization to aziridine 3 occurs in good yield.
When the addition was performed on isobutylidene
malonate, good conversion and 80% e.e. were observed.
Herein, we report the results obtained in the separation
of the product enantiomers. The absolute configuration
of the major isomer of 3-isopropylaziridine-2,2-dicar-
boxylate was determined through its transformation
The conjugate addition of hydroxylamine derivatives to
chiral imide acceptors promoted by Lewis acids is of
particular interest within our laboratory.1 The 1,4-
adduct is a useful intermediate for the synthesis of
chiral non-racemic aziridines.2 Recently we turned our
attention to alkylidene malonates as good Michael
acceptors.3 In the previous work we reported the addi-
tion of N,O-bis (trimethylsilyl)hydroxylamine to an
a,b-unsaturated malonate in the presence of a chiral
Lewis acid3 and the conversion of the 1,4-adduct to the
corresponding aziridine-2,2-dicarboxylate.4
into
the
corresponding
(S)-phenylethylamido
derivative.
The procedure is exemplified by the reactions outlined
in Scheme 1 and involves the conjugate addition of
commercially available N,O-bis(trimethylsilyl) hydroxyl-
amine to a substrate in the presence of a catalytic
amount of Cu(OTf)2 and chiral bisoxazoline ligand.4
The subsequent cyclization occurs under very mild
2. Results and discussion
For our investigation an uncatalyzed reaction was car-
ried out and the racemic mixture was submitted to
Scheme 1. Synthesis of chiral aziridine-2,2-dicarboxylate.
* Corresponding author. Tel.: +39 051 2099570; fax: +39 051 2099456; e-mail: cardillo@ciam.unibo.it
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00341-5

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G. Cardillo et al. / Tetrahedron: Asymmetry 13 (2002) 1411–1415
resolution. This separation could be carried out accord-
ing to the observation that the regiospecific hydrolysis
of benzoylamido diester 4 may be performed under
very mild basic conditions.5
mation into the chiral amide was obtained through the
formation of the intermediate acid chloride of 5, pre-
pared by reaction with oxalyl chloride and an equi-
molar amount of DMF in dry benzene.7 The moisture-
sensitive acid chloride, used without further purification
in the coupling with (S)-(−)-a-methylbenzylamine, fur-
nished the chiral amide 6 as a diastereomeric mixture in
70% yield.
The monoester 5 is a useful intermediate that can be
easily transformed in the diastereomeric appropriate
amide utilizing chiral (S)-(−)-a-methylbenzylamine. For
this purpose, the racemic compound 3 was prepared
and the nitrogen atom of the aziridine was protected by
treatment with benzoyl chloride in CH2Cl2 in the pres-
ence of TEA and DMAP. The benzamide 4 was
obtained in quantitative yield. In the NMR spectrum of
4 recorded in CDCl3 the signal of a methyl ester that
resonates at 3.9 ppm can be seen, almost unchanged
with respect to the starting compound 3, and the other
ester group at 3.3 ppm, strongly shielded by the pro-
tecting benzoyl group (Fig. 1). The amide 4 is a very
stable molecule and regioselective hydrolysis of the
more shielded methyl ester was effected by treatment
with 1 equiv. of KOH in MeOH over 5 days at room
temperature (Scheme 2).
A slurry of the diastereomeric mixture of amides 6 was
then submitted to slow crystallization in MeOH/water
(9:1). After 2 days, complete diastereomeric separation
was obtained, since the diastereoisomer 6a crystallised
(>99% d.e.), with 6b remaining in solution (84% d.e.).
The diastereomeric excess of each derivative was deter-
mined by HPLC analysis.
The structure of 6a has been determined by single
crystal X-ray diffraction. The configuration and the
conformation of 6a in the crystal lattice, shown in Fig.
2, show that the asymmetric carbons of the aziridine
ring possess 2R and 3S configuration respectively. Fur-
,
thermore, the distance between (O)3 and (H)2 (2.34 A)
This unexpected result may be rationalised on the basis
of the structure of 4, minimized with AM1 semiempiri-
cal calculation.6 The structure shows, for a stable con-
formation, the trans relationship between the isopropyl
group and the more shielded methyl ester resonating at
3.3 ppm. The 1H NMR spectra of aziridine 3, the
diester 4 and the monoester 5 are reported in Fig. 1.
suggests the presence of an electrostatic interaction
between the methyl ester carbonyl group and the amide
NH. The (O)3ꢀ(H)2ꢀ(N)2 angle (124.76°) prevents the
confirmation of a classical hydrogen bond. Selected
bond lengths and angles are reported in Table 1. The
synthetic pathway leading from aziridine 3 to amide 6,
was performed even on the enantiomerically enriched
compound obtained from the chiral Lewis acid-cata-
lyzed 1,4-addition, followed by cyclization to the
aziridine. The ratio of 6a and 6b was determined by
HPLC analysis. The most abundant isomer turned out
1
From analysis of the H NMR spectra of 4 and 5 it can
be seen that the more shielded methyl ester is exclu-
sively hydrolyzed (being the less sterically hindered
one), while the methyl ester resonating at 3.9 ppm is
resistant to the basic hydrolytic conditions. Transfor-
1
Figure 1. Semiempirical calculated (AM1) structure of aziridine 4 and H NMR spectra of 3–5.

G. Cardillo et al. / Tetrahedron: Asymmetry 13 (2002) 1411–1415
1413
Scheme 2. Regioselective hydrolysis of aziridine diester 4 and synthesis of diastereomers 6. Reagents and conditions: (i) PhCOCl,
TEA, CH2Cl2, rt; (ii) KOH (1 equiv.), MeOH, rt, 4 days; (iii) COCl2, DMF, benzene; (iv) TEA, (S)-(−)-a-methylbenzylamine.
establish the stereochemical course of the conjugate
addition reaction catalyzed by chiral bisoxazoline–Cu
complex. The addition is the key step of the synthesis of
aziridine-2,2-dicarboxylate since it is responsible for the
final stereochemistry of the heterocylic product.
4. Experimental
4.1. General procedures
Unless stated otherwise, chemicals were obtained from
commercial sources and used without further purifica-
tion. CH2Cl2 was distilled from P2O5. Flash chromatog-
raphy was performed on Merck silica gel 60 (230–400
mesh). NMR Spectra were recorded with a INOVA
Varian spectrometer 300 MHz or with a Gemini Varian
spectrometer 200 MHz. Chemical shifts were reported
as l values relative to the solvent peak of CDCl3 set at
Figure 2. X-Ray structure of aziridine 6a.
l 7.27 (1H NMR) or l 77.0 (13C NMR). Infrared
spectra were recorded with an FT-IR Nicolet 205 spec-
trometer. GC–MS analyses were performed on HP5890
to be 6a, allowing to deduce that the first step of the
1,4-addition of N,O-bis(trimethylsilyl)hydroxylamine to
isobutylidene malonate furnished (3S)-2 as major
isomer.
series II cromatograph with HP5971 mass detector.
Optical rotation powers were recorded with Perkin–
Elmer polarimeter 343. HPLC analyses were performed
on HP1090 liquid chromatograph equipped with UV
detector. CHIRALCEL-OD chiral column, isocratic
analysis with 90:10 hexane/isopropanol as eluent, 0.5
mL/min solvent flow, UV detector at 214.4 and 220.4
nm. MS analyses were performed with a HP 1100 series
mass spectrometer single quadrupole electrospray ion-
ization interface (ESI). Compounds 1–3 have been pre-
pared following the procedure reported in the previous
paper.
3. Conclusion
The absolute configuration of aziridine-2,2-dicarboxyl-
ates was determined through their transformation into
the corresponding diastereomeric (S)-(−)-a-methylben-
zylamido derivatives. The data obtained allows us to

1414
G. Cardillo et al. / Tetrahedron: Asymmetry 13 (2002) 1411–1415
,
Table 1. Selected bond lengths (A) and angles (°) for 6a
4.4. Synthesis of amide 6
,
,
Bond
(A)
Bond
(A)
To a stirred solution of aziridine 5 (1 mmol, 0.291 g) in
dry benzene (10 mL), DMF (2 mmol, 0.15 mL) and
oxalyl chloride (2 mmol, 0.128 mL) were added at rt
under an inert atmosphere. After 1 h, the solvent was
reduced to 5 mL under vacuum and another portion of
dry benzene (5 mL) was added. To this solution, under
a nitrogen atmosphere, (S)-(−)-a-methylbenzylamine
(1.1 mmol, 0.141 mL) and TEA (1.1 equiv., 0.153 mL)
were added. After 1 h the reaction was quenched with
water (5 mL), diluted with EtOAc (10 mL) and washed
with 0.1 M HCl (10 mL), 0.1 M NaHCO3 (10 mL) and
brine (10 mL). The organic layer was dried over
Na2SO4 and solvent removed under reduced pressure.
Compound 6 was obtained as a yellow oil in 70% yield,
after flash chromatography on silica gel (toluene/ace-
tone, 9/1). Crystallization performed in MeOH/H2O
(10/1) allowed separation of 6a and 6b.
N(1)ꢀC(2)
N(1)ꢀC(3)
N(1)ꢀC(17)
N(2)ꢀC(1)
N(2)ꢀC(9)
N(2)ꢀH(2)
O(1)ꢀC(1)
1.456(2)
1.439(3)
1.411(2)
1.332(2)
1.467(2)
0.93(3)
O(3)ꢀC(7)
O(4)ꢀC(17)
C(1)ꢀC(2)
C(2)ꢀC(3)
C(2)ꢀC(7)
C(17)ꢀC(18)
1.185(2)
1.211(2)
1.525(2)
1.518(2)
1.505(2)
1.483(2)
1.217(2)
Angle
(°)
Angle
(°)
C(2)ꢀN(1)ꢀC(3)
N(1)ꢀC(2)ꢀC(3)
N(1)ꢀC(3)ꢀC(2)
C(1)ꢀN(2)ꢀC(9)
C(1)ꢀN(2)ꢀH(2)
C(9)ꢀN(2)ꢀH(2)
O(1)ꢀC(1)ꢀN(2)
63.2(1)
57.8(1)
58.9(1)
122.0(2)
121(2)
117(2)
124.4(2)
O(1)ꢀC(1)ꢀC(2)
N(2)ꢀC(1)ꢀC(2)
O(4)ꢀC(17)ꢀN(1)
O(4)ꢀC(17)ꢀC(18)
N(1)ꢀC(17)ꢀC(18)
C(17)ꢀN(1)ꢀC(2)
C(17)ꢀN(1)ꢀC(3)
118.6(2)
117.0(1)
120.2(2)
123.7(2)
115.7(1)
124.1(1)
121.5(1)
Compound 6a: mp 123–125°C; IR (film): 3370, 3071,
2959, 2872, 1726, 1679, 1600, 1533, 1447 cm−1; 1H
NMR (CDCl3): l 1.06 (d, 3H, J=7.0 Hz), 1.27 (d, 3H,
J=6.2 Hz), 1.46 (d, 3H, J=7.0 Hz), 1.40–1.60 (m, 1H),
3.06 (d, 1H, J=9.8 Hz), 3.98 (s, 3H), 4.80–4.94 (m,
1H), 6.86–6.91 (m, 2H), 7.16–7.19 (m, 3H), 7.28–7.52
(m, 3H), 7.83–7.93 (m, 3H); 13C NMR (CDCl3): l 19.2,
21.0, 21.3, 29.1, 49.3, 52.5, 53.6, 55.3, 125.8, 127.2,
127.9, 128.4, 128.5, 132.2, 134.3, 142.1, 161.8, 169.1,
175.8; MS-ESI m/z 395 (M+1); [h]2D0=−151.0 (c 1.2,
CHCl3).
4.2. Synthesis of N-benzoylaziridine 4
Benzoyl chloride (1.1. mmol, 0.127 mL) in CH2Cl2 (5
mL) was added dropwise to a stirred solution of
aziridine 3 (1 mmol) and TEA (1.2 mmol, 0.167 mL) in
CH2Cl2 (5 mL). The reaction was allowed to stir for 2
h and then quenched with water. After diluting with
CH2Cl2 (20 mL) and washing with water, the organic
layer was dried over Na2SO4 and solvent removed
under reduced pressure. Compound 4 was obtained in
97% yield after flash chromatography on silica gel as a
white solid (cyclohexane/Et2O, 8/2). Compound 4: mp
81–84°C; IR (film): 3059, 2972, 1739, 1693, 1428, 1242
Compound 6b: IR (film): 3373, 3070, 2961, 2871, 1724,
1
1686, 1609, 1531, 1440 cm−1; H NMR (CDCl3): l 1.01
(d, 3H, J=6.6 Hz), 1.10 (d, 3H, J=6.8 Hz), 1.25 (d,
3H, J=5.2 Hz), 1.40–1.60 (m, 1H), 2.99 (d, 1H, J=9.6
Hz), 4.01 (s, 3H), 4.80–4.94 (m, 1H), 7.18–7.58 (m, 8H),
7.80–8.02 (m, 3H); 13C NMR (CDCl3): l 18.9, 20.8,
21.8, 28.9, 49.5, 52.3, 53.4, 55.0, 125.6, 127.3, 127.8,
128.2, 128.6, 132.0, 134.1, 142.0, 161.6, 169.0, 175.7;
MS-ESI m/z 395 (M+1); [h]2D0=+75.0 (c 0.9, CHCl3).
1
cm−1; H NMR (CDCl3): l 1.10 (d, 3H, J=6.6 Hz),
1.23 (d, 3H, J=6.3 Hz), 1.30–1.41 (m, 1H), 3.14 (d, 1H,
J=9.6 Hz), 3.34 (s, 3H), 3.94 (s, 3H), 7.38–7.60 (m,
3H), 8.10–8.14 (m, 2H); 13C NMR (CDCl3): l 18.8,
20.8, 29.7, 52.7, 52.9, 53.0, 128.3, 128.6, 130.0, 132.9,
165.0, 165.3, 175.6; MS m/z 305 (6), 290 (11), 200 (13),
105 (100), 77 (33).
4.5. X-Ray data collection and structure refinement
4.3. Partial hydrolysis of aziridine 4
A suitable crystal of compound 6a was mounted on a
glass fiber in air on a Bruker-AXS SMART CCD area
detector diffractometer. The detector to crystal distance
was 5 cm. The diffraction experiment was carried out at
rt. The initial cell parameters and an orientation matrix
were obtained from least-squares refinement on reflec-
tions measured in three different sets of 20 frames each,
in the range −15<q<15°. The intensity data comprising
a hemisphere were collected using the ꢀ-scan technique
with frame width set at 0.3°. The first 50 frames were
remeasured at the end of data collection to monitor
decay. The collected frames were then processed for
integration by software SAINT and an empirical
absorption correction was applied by SADABS.8 The
structure was solved by direct methods (SIR-97)9 and
To a stirred solution of aziridine 4 (0.5 mmol, 150 mg)
in MeOH (5 mL) at rt, KOH (1 equiv., 2 mL of 0.25 M
solution in MeOH) was added in one portion. The
mixture was left stirring at rt for 4 days, quenched with
diluted HCl and then solvent removed under reduced
pressure. The residue was diluted with EtOAc and
washed twice with water. The organic layer was dried
over Na2SO4 and solvent removed under reduced pres-
sure to give aziridine 5 in 81% yield. Compound 5: IR
(film): 3131, 2965, 1752, 1706, 1283 cm−1; 1H NMR
(CDCl3): l 1.09 (d, 3H, J=6.6 Hz), 1.21 (d, 3H, J=6.6
Hz), 1.31–1.51 (m, 1H), 3.07 (d, 1H, J=9.02 Hz), 3.94
(s, 3H), 6.51–6.82 (bs, 1H), 7.35–7.51 (m, 3H), 8.04–
8.11 (m, 2H); 13C NMR (CDCl3): l 18.6, 20.6, 29.7,
52.6, 52.9, 53.2, 128.2, 128.5, 132.7, 133.6, 165.6, 167.3,
175.8; MS m/z 291 (2), 248 (7), 142 (4), 105 (100), 77
(24).
2
refined by full-matrix least-squares on Fo using
SHELXTL.10 Anisotropic displacement parameters
were assigned to all non-hydrogen atoms in the struc-
ture. Hydrogen atom on nitrogen was experimentally

G. Cardillo et al. / Tetrahedron: Asymmetry 13 (2002) 1411–1415
1415
located while the others were placed on idealized
positions.
2000), by the University of Bologna (funds for selected
topics) and by ISOF (CNR-Bologna).
Crystallographic studies of 6a: C23H26N2O4, M=394.46,
monoclinic, space group P21 (No. 4), a=7.6491(5),
References
,
b=15.960(1), c=9.1966(6) A, i=109.950(2)°, V=
3
1055.4(1) A , T=293(2) K, Z=2, Dcalcd=1.241 mg/m3,
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v(Mo Ka)=0.085 mm−1, 9861 reflections collected,
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lations. The value of the goodness-of-fit indicator was
1.047. Final R1(F)=0.0495 [I>2|(I)] and wR2(F2)=
0.1449 (all data).
Least-squares planes (x,y,z in crystal coordinates) and
deviations from them (* indicates atom used to define
plane)
−0.3755 (0.0299) x+15.7968 (0.0232) y−
1.0063 (0.1140) z=9.6896 (0.0404)
* 0.0065 (0.0065) C1
* −0.0062 (0.0061) O1
* 0.0073 (0.0073) N2
* −0.0077 (0.0077) H2
7. (a) Maruyama, H.; Shiozaki, M.; Hiraoka, T. Bull. Chem.
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Polidori, G.; Camalli, M.; Spagna, R. J. Appl. Crystal-
logr. 1999, 32, 115.
Rms deviation of fitted atoms=0.0070
The crystallographic data for 6a have been deposited
with the Cambridge Crystallographic Data Centre as
supplementary publication numbers CCDC 186973.
Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge,
CB2 1EZ, UK [fax: +44(0)-1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk].
10. Sheldrick, G. M. SHELXTLplus Version 5.1 (Windows
NT Version) Structure Determination Package; Bruker
Analytical X-ray Instruments Inc.: Madison, WI, 1998.
Acknowledgements
This work was supported by MURST (60% and Cofin