The origin of chemical and configurational stability of chiral nonracemic tert-butyl aziridinecarboxylate anions

Article abstract of DOI:10.1002/1099-0690(200107)2001:13<2589::AID-EJOC2589>3.0.CO;2-Y

The origin of good chemical and configurational stability of aziridine ester anions derived from (R)-(-)-phenylglycinol has been investigated. Kinetic acidity seems to play an important role in the deprotonation step and chemical stability of the anionic species. Spectroscopic investigations showed that the good overall retention of configuration was governed by the directing effect of the nitrogen atom, which acts as a stereogenic centre in the alkylation step of the enolate intermediate.

Full text of DOI:10.1002/1099-0690(200107)2001:13<2589::AID-EJOC2589>3.0.CO;2-Y

FULL PAPER
The Origin of Chemical and Configurational Stability of Chiral Nonracemic
tert-Butyl Aziridinecarboxylate Anions
[a]
Valerie Alezra, Martine Bonin,*[a] Laurent Micouin,*[a] Clotilde Policar,[b] and
´
Henri-Philippe Husson[a]
Professor Jean Normant on the occasion of his 65th birthday
Keywords: Aziridine / Configurational stability / Nitrogen inversion / Kinetic acidity / Quaternary amino esters
The origin of good chemical and configurational stability of
that the good overall retention of configuration was governed
aziridine ester anions derived from (R)-(−)-phenylglycinol by the directing effect of the nitrogen atom, which acts as a
has been investigated. Kinetic acidity seems to play an im-
portant role in the deprotonation step and chemical stability
of the anionic species. Spectroscopic investigations showed
stereogenic centre in the alkylation step of the enolate inter-
mediate.
Introduction
and moderate d.s. (33Ϫ60%) was obtained when starting
from its diastereomer 1(2R) (Scheme 1).
The preparation of chemically and configurationally
stable three-membered ring anionic species is of particular
interest for the efficient asymmetric elaboration of synthet-
ically useful starting materials.[1] Since the pioneering works
of Walborsky[2,3] and Boche[4] in the field of cyclopropane
chemistry, it is known that cyclopropyl anions with an elec-
tron-withdrawing group can react as CϪLi or delocalised
carbanions. These two reactive species have been charac-
terised by X-ray crystallography for cyclopropane anions
with stabilising functional groups, and this shows that the
nature of the functional groups can dramatically influence
the geometry of the relative anionic species.[5] For cyclopro-
pane ester anions, both CϪLi,[6] planar[7] or pyramidal[8]
enolate intermediates have been proposed to explain their
reactivity.
The chemistry of aziridinyl ester anions was first investig-
ated by Seebach and co-workers,[9,10] who reported that all
attempts to generate such species led only to degradation
and/or self-condensation. However, when the ester group
was replaced with a thiol ester function, deprotonation and
functionalisation of several aziridine thiol esters at very low
temperature (Ϫ100 °C) could be obtained. Interestingly, re-
tention of configuration was observed for compound 1(2S),
Scheme 1
The authors first explained this apparent memory of
chirality by the formation of a pyramidal enolate as a react-
ive species.[10] Another explanation was furnished several
years later by Seebach in his review on the SRS principle
(Self-Regeneration of Stereocenters), based on the chirality
of the aziridine nitrogen atom.[11] We recently reported that
aziridine esters 2 could be deprotonated and functionalised
under milder conditions, with overall good to excellent re-
tention of configuration.[12] In this article we disclose our
full results in this field and our investigations on the origin
of improved chemical and configurational stability of such
species.
[a]
´
´
`
Laboratoire de Chimie Therapeutique associe au CNRS et a
´
´
´
l’Universite Rene Descartes (UMR 8638), Faculte des Sciences
Results and Discussion
Pharmaceutiques et Biologiques,
4, av. de l’Observatoire, 75270 Paris cedex 06, France
Fax: (internat.) ϩ 33-1/43291403
Aziridines 2Ϫ4 were prepared as 1:1 diastereomeric mix-
tures according to a reported procedure,[13] and each dias-
tereomer could be separated by column chromatography
(Scheme 2, Table 1).
E-mail: bonin@pharmacie.univ-paris5.fr
micouin@pharmacie.univ-paris5.fr
[b]
Laboratoire de Chimie Bioorganique et Bioinorganique ERS
´
1824, Universite Paris XI,
91405 Orsay, France
Eur. J. Org. Chem. 2001, 2589Ϫ2594
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/0713Ϫ2589 $ 17.50ϩ.50/0
2589

V. Alezra, M. Bonin, L. Micouin, C. Policar, H.-P. Husson
FULL PAPER
Table 2. Functionalisation of Aziridine 2(2S)
Compound
Eϩ
Yield [%][a] Yield [%][a] dr [%][b]
[no DMPU] [with DMPU]
8a(2R)
8b(2S)
8c(2S)
8d(2S)
8e(2S)
8f(2R)
8g(2R)
(CH3)3SiCl
CH3I
CH2ϭCHCH2Br
BrCH2CO2tBu
ClCH2Ph
cyclohexanone
PhCHO
41
47
44
Ϫ
Ϫ
21
35
37
59
64
54
28
Ϫ
Ͼ 98:2
Ͼ 98:2
Ͼ 98:2
Ͼ 98:2
Ͼ 98:2
Ͼ 98:2
61:39
Scheme 2
Ϫ
[a] Yield of isolated product. Ϫ [b] Determined by 1H NMR spectro-
scopy of the crude reaction mixture.
Table 1. Preparation of Aziridines 2Ϫ4
Compound
X
R
Yield [%][a]
2
3
4
OMe
OMe
H
tBu
Et
tBu
80
94
52
The absolute configuration was established for com-
pound 8e(2S) by chemical correlation with (S)-α-benzylser-
ine (10)[15] and assigned for other aziridines by comparison
[a]
1
of H and 13C NMR spectra (Scheme 5).
Combined yield of diastereomers after chromatographic separa-
tion.
Absolute configuration of the newly created asymmetric
centre was established by chemical correlation of com-
pound 2(2R) with -serine (6) (Scheme 3) and assigned for
other aziridines by comparison of NMR spectra.
Scheme 5. Reagents and conditions: a) 20% aq. HClO4, 80 °C, 3 h,
31%; b) H2, Pd(OH)2, EtOH/H2O (1:1), 100%
When performed on aziridine 2(2R), the same depro-
tonation conditions led only to self-condensation product
11.[16] In contrast, in a 5:1 mixture of DME/Et2O, this aziri-
dine could be deprotonated and functionalised in a moder-
ate yield (competitive self-condensation could not be com-
pletely avoided) but with good to excellent retention of con-
figuration (Scheme 6 and Table 3).
Scheme 3. Reagents and conditions: a) 20% aq. HClO4, 80 °C, 15 h,
48%; b) H2, Pd(OH)2, EtOH/H2O (1:1), 100%
At first, deprotonation of compound 3(2S) with LDA led
only to self-condensation product 7, as already observed in
the cyclopropane series.[14] However, the tert-butyl ester
2(2S) could be deprotonated by LDA in THF and reacted
with various electrophiles at Ϫ78 °C, with or without
DMPU (Scheme 4).
Scheme 6
Table 3. Functionalisation of Aziridine 2(2R)
Compound
Eϩ
Yield [%][a]
dr [%][b]
8a(2S)
8b(2R)
8c(2R)
8d(2R)
(CH3)3SiCl
CH3I
CH2ϭCHCH2Br
BrCH2CO2tBu
38[c]
48
49
89:11
98:2
94:6
95:5
Scheme 4
30
The use of other bases led only to starting material
(NaH, LiHMDS), epimerised aziridine 2 (with KHMDS,
dr ϭ 80:20) or addition of the base to the carboxylic func-
tion (tBuLi) without deprotonation. Under optimised con-
ditions (LDA, THF, Ϫ78 °C), functionalisation of aziridine
2(2S) occurred with complete retention of configuration at
[a] Yield of isolated product. Ϫ [b] Determined by 1H NMR spectro-
[c]
scopy of the crude reaction mixture. Ϫ Diastereomers were not
separated.
In the case of aziridine thiol esters 1, Seebach and co-
the reactive centre (with benzaldehyde as electrophile, con- workers explained the excellent overall retention of config-
trol of the second asymmetric centre was fairly poor) uration by the formation of a transient pyramidal enol-
(Table 2).
2590
ate.[10] However, the hypothesis of a configurationally stable
Eur. J. Org. Chem. 2001, 2589Ϫ2594

Chiral Nonracemic tert-Butyl Aziridinecarboxylate Anions
FULL PAPER
C-lithiated intermediate, which has been characterised by DME is required. Finally, the difference in the chemical and
Vedejs and co-workers for ‘‘non-stabilised’’ metallated aziri- configurational stability of the reactive species in the two
dines,[17] cannot be ruled out, especially if one considers diastereomeric series can be explained by the difference of
that aziridine ester anions bearing a potential chelating stability between the diastereomeric enolates 12a and 12b
group (MeO) proved to be more stable than anions of com- (Figure 2).
pounds 1.[18] We therefore decided to investigate the mech-
anism responsible for the good configurational and chem-
ical stability in our system.
We first studied the role of the nitrogen lone pair. H
1
NMR spectra of compounds 2(2S) and 2(2R) showed the
presence of a small amount (8%) of invertomers in
[D6]THF and this proportion remained unchanged at low
temperature [Ϫ70 °C for 2(2S) and Ϫ100 °C for 2(2R)]. On
the other hand, coalescence could be observed in
[D6]DMSO for both diastereomers around 333 K, and the
free energy of inversion was calculated (about 16 kcal
molϪ1). These results indicate that the nitrogen atom can
be considered as a stereogenic centre, because of this high
inversion energy barrier. The absolute configuration of the
nitrogen atom for the major invertomers of both diastereo-
Figure 2. Relative stabilities of the enolates 12a and 12b
1
mers was determined with JH-C coupling constants (Fig-
ure 1).[19] It appears that in both cases, the nitrogen lone
Steric hindrance between aziridines protons and methyl-
pair is anti to the acidic proton.
enic protons of the chiral moiety probably destabilises enol-
ate 12b, and leads to an enhanced self-condensation rate
(chemical instability) and epimerisation through nitrogen
inversion (configurational instability).
Figure 1. Relative configuration of the nitrogen atom
Conclusion
We have shown that it is possible to generate and func-
We then tried to characterise the reactive species. Low-
tionalise chemically and configurationally stable aziridine
1
temperature H NMR experiments did not give significant
ester anions. The deprotonation rate is highly dependent on
results. However, low-temperature infrared experiments
the kinetic acidity of the substrate, and this can be im-
could be performed on deprotonated 2(2S) (Ϫ65 °C, THF,
proved by the presence of a chelating group on the molecule
same concentration as for alkylations). The IR spectra
or by the use of DME as a solvent. Several spectroscopic
˜
showed complete disappearance of the CO band (ν ϭ
investigations proved that the reactive species is an enolate,
and that the overall good retention of configuration was
governed by the directing effect of the nitrogen atom, which
acts as a stereogenic centre in the alkylation step.
1739 cmϪ1), and appearance of a new less intense band at
1710 cmϪ1, this can be attributed to CϭC vibration of an
enolate.[20,21] Disappearance of a band at 1408 cmϪ1 (CH
bending of the acidic proton) was also noticed. Similar re-
sults were obtained with compound 2(2R) in a mixture of
DME/Et2O at Ϫ65 °C. All these results seem to indicate
that the reactive species are enolates. The retention of con-
figuration can be explained by an approach of electrophiles
anti to the nitrogen lone pair.
Experimental Section
General Procedures: All reactions involving air-sensitive materials
were carried out under argon. Sensitive liquids were transferred by
a syringe. Product purification was performed by flash chromato-
We then investigated the origin of the improved chemical
stability of the aziridine anions. Standard deprotonation graphy on silica gel (Merck, 230Ϫ400 mesh). THF was successively
distilled from sodium benzophenone and LAH. DME was distilled
from sodium benzophenone. Ϫ Routine infrared spectra (IR) were
recorded neat with a PerkinϪElmer 1600 spectrophotometer. Low-
temperature IR spectra were recorded with an FTIR Bruker IFS66
spectrometer driven by an Opus 2.2 program. A fluorine cell was
mounted on a cryogenic device Graseby Specac equipped with a
temperature reader (P/N 20120). Low temperature (Ϫ65 °C) was
obtained with EtOH/dry ice in the cold finger. The main chamber
of the Graseby Specac device was maintained under argon. Ϫ Op-
conditions (LDA, THF, Ϫ78 °C) used with compound
4(2S), resulted in mainly starting material. This surprising
result showed that the chelating methoxy group improves
the kinetic acidity of aziridines, and therefore slows down
the self-condensation rate.[22] A similar kinetic effect has al-
ready been observed by Vedejs and co-workers in the pre-
paration of nonstabilised aziridine anions by a tinϪlithium
exchange.[18] For steric reasons, stabilisation of the trans-
ition state in the deprotonation step does not occur for dias-
tical rotations of CHCl3 or H2O solutions were measured at 20 °C
1
tereomer 2(2R), and an intermolecular stabilisation by with a PerkinϪElmer 141 automatic polarimeter. Ϫ H NMR and
Eur. J. Org. Chem. 2001, 2589Ϫ2594
2591

V. Alezra, M. Bonin, L. Micouin, C. Policar, H.-P. Husson
FULL PAPER
13C NMR spectra were recorded at 300 MHz and 75 MHz, respect-
ively, with a Bruker AC 300 spectrometer. Ϫ Mass spectra were
recorded in the chemical ionisation mode (NH3) with an AEI MS-
(dd, J ϭ 6.4, 3.2 Hz, 1 H), 2.05 (dd, J ϭ 2.2, 1.1 Hz, 1 H), 1.66 (dd,
J ϭ 6.4, 1.1 Hz, 1 H), 1.49 (s, 9 H), 1.46 (d, J ϭ 6.5 Hz, 1 H). Ϫ
13C NMR (75 MHz, CDCl3): δ ϭ 170.1, 143.7, 128.3, 127.2, 127.0,
9 spectrometer. High-resolution mass spectra were obtained with a 81.3, 69.9, 38.9, 33.8, 28.1, 23.4. Ϫ HRMS calcd. for C15H22NO2:
Kratos MS 80RF spectrometer.
248.1651, found 248.1646
General Procedure for the Preparation of Aziridines. ؊ Preparation
of Aziridines 2(2R) and 2(2S) is Typical: To a solution of tert-butyl
2,3-dibromopropionate (1.60 g, 5.56 mmol) in ethanol (100 mL)
was added (R)-methoxyphenylglycinol (0.84 g, 5.56 mmol) at Ϫ20
°C. After stirring for 5 min, triethylamine (2.32 mL, 16.7 mmol)
was added and the reaction mixture was stirred for 48 h. The solv-
ent was then removed (evaporator), and the resulting mixture was
diluted with diethyl ether. The solid triethylamine salts were filtered
off and washed twice with ether. After removal of the solvent, the
residue was purified by flash chromatography on silica gel (95:5
CH2Cl2/cyclohexane eluent) to give 1.22 g (80%) of 2 as a colour-
less oil [402 mg of diastereomer (2S), 378 mg of mixture and
443 mg of diastereomer (2R)]. Ϫ C16H23NO3 (277.4): calcd. C
69.29, H 8.36, N 5.05; found C 68.92, H 8.35, N 4.93.
Self-Condensation Product 7(2R,2ЈS): Analytical TLC on silica gel,
20:80 AcOEt/cyclohexane, Rf ϭ 0.20. Ϫ IR (neat): 2927, 1722,
1
1603 cmϪ1. Ϫ MS: 453 [M ϩ 1]. Ϫ H NMR (300 MHz, CDCl3):
δ ϭ 7.17Ϫ7.40 (m, 10 H), 3.56Ϫ3.95 (m, 6 H), 3.52 (dd, J ϭ 9.6,
4.7 Hz, 1 H), 3.40 (s, 3 H), 3.35 (s, 3 H), 2.97 (dd, J ϭ 6.7, 2.9 Hz,
1 H), 2.81 (s, 1 H), 2.77 (dd, J ϭ 7.9, 4.7 Hz, 1 H), 2.70 (s, 1 H),
1.97 (s, 1 H), 1.50 (d, J ϭ 6.7 Hz, 1 H), 0.85 (m, 3 H). Ϫ 13C NMR
(75 MHz, CDCl3): δ ϭ 200.3, 166.0, 140.0, 139.6, 128.4, 127.8,
78.6, 78.1, 73.6, 65.9, 61.7, 59.2, 59.1, 49.4, 42.4, 39.9, 34.2, 13.6.
General Procedure for the Alkylation of Compound 2(2S). ؊ With
DMPU: To a solution of aziridine 2(2S) (150 mg, 0.54 mmol) in
dry THF (10 mL) at Ϫ78 °C under argon was added LDA (1.5
 in cyclohexane, 722 µL, 1.08 mmol). After 1 h, the electrophile
(1.62 mmol) and the DMPU (196 µL, 1.62 mmol) were consecut-
ively added. The reaction mixture was maintained at Ϫ78 °C for
7 h and then quenched with saturated aqueous NH4Cl solution
(5 mL). The cooling bath was removed, the solution was allowed
to warm to room temperature and diluted with ether (5 mL). The
aqueous layer was separated and extracted with two 10-mL por-
tions of CH2Cl2, and the combined organic phases were dried with
MgSO4, filtered and concentrated. The crude reaction product was
purified by flash chromatography on silica gel to give the pure al-
kylated aziridines as colourless oils. Ϫ Without DMPU: To a solu-
tion of aziridine 2(2S) (140 mg, 0.50 mmol) in dry THF (10 mL) at
Ϫ78 °C under argon was added LDA (1.5  in cyclohexane, 674
µL, 1.01 mmol). After 1 h, the electrophile (1.52 mmol) was added.
The reaction mixture was maintained at Ϫ78 °C for 7 h and then
quenched with saturated aqueous Na2CO3 solution (5 mL). The
cooling bath was removed, the solution was allowed to warm to
room temperature and diluted with EtOAc (5 mL). The aqueous
layer was separated and extracted with two 10-mL portions of
CH2Cl2, and the combined organic phases were dried with MgSO4,
filtered and concentrated. The crude reaction product was purified
by flash chromatography on silica gel to give the pure alkylated
aziridines as colourless oils.
Aziridine 2(2S): Analytical TLC on silica gel, 95:5 CH2Cl2/cyclo-
hexane, Rf ϭ 0.25. Ϫ [α]D ϭ Ϫ65 (c ϭ 0.7, CHCl3). Ϫ IR (neat):
2979, 2929 and 1738 cmϪ1. Ϫ MS: 278 [M ϩ 1]. Ϫ 1H NMR
(300 MHz, CDCl3): δ ϭ 7.45Ϫ7.25 (m, 5 H), 3.70 (dd, J ϭ 9.8,
7.7 Hz, 1 H), 3.61 (dd, J ϭ 9.8, 4.8 Hz, 1 H), 3.37 (s, 3 H), 2.69
(dd, J ϭ 7.7, 4.8 Hz, 1 H), 2.38 (dd, J ϭ 6.3, 3.4 Hz, 1 H), 2.01 (dd,
J ϭ 3.4, 1.0 Hz, 1 H), 1.50 (s, 9 H), 1.42 (dd, J ϭ 6.3, 1.0 Hz, 1 H).
Ϫ
13C NMR (75 MHz, CDCl3): δ ϭ 169.9, 139.6, 128.1, 127.5,
80.8, 77.8, 73.3, 59.0, 40.0, 31.1, 27.9.
Aziridine 2(2R): Analytical TLC on silica gel, 95:5 CH2Cl2/cyclo-
hexane, Rf ϭ 0.20. Ϫ [α]D ϭ ϩ15 (c ϭ 1.1, CHCl3). Ϫ IR (neat):
2979, 2929 and 1738 cmϪ1. Ϫ MS: 278 [M ϩ 1]. Ϫ 1H NMR
(300 MHz, CDCl3): δ ϭ 7.42Ϫ7.23 (m, 5 H), 3.72 (dd, J ϭ 9.8,
7.9 Hz, 1 H), 3.54 (dd, J ϭ 9.8, 4.5 Hz, 1 H), 3.34 (s, 3 H), 2.75
(dd, J ϭ 7.9, 4.5 Hz, 1 H), 2.39 (dd, J ϭ 3.3, 1.0 Hz, 1 H), 1.98 (dd,
J ϭ 6.4, 1.0 Hz, 1 H), 1.87 (dd, J ϭ 6.4, 3.3 Hz, 1 H), 1.40 (s, 9 H).
Ϫ
13C NMR (75 MHz, CDCl3): δ ϭ 169.7, 139.8, 128.0, 127.2,
127.1, 80.6, 78.0, 73.1, 58.8, 35.6, 35.5, 27.7.
Aziridine 3(2S): Analytical TLC on silica gel, 95:5 CH2Cl2/cyclo-
hexane, Rf ϭ 0.48. Ϫ [α]D ϭ Ϫ79 (c ϭ 0.98, CH2Cl2). Ϫ IR (neat):
1
2983 and 1740 cmϪ1. Ϫ MS: 250 [M ϩ 1]. Ϫ H NMR (300 MHz,
General Procedure for Alkylation of Compound 2(2R): To a solution
of aziridine 2(2R) (140 mg, 0.50 mmol) in a mixture of dry DME
(5 mL) and Et2O (1 mL) at Ϫ78 °C under argon was added LDA
(1.5  in cyclohexane, 674 µL, 1.01 mmol). After stirring for 15
min, the electrophile (1.52 mmol) was added. The reaction mixture
was maintained at Ϫ78 °C for 2 h and then quenched with satur-
ated aqueous Na2CO3 solution (5 mL). The cooling bath was re-
moved, the solution was allowed to warm to room temperature and
diluted with EtOAc (5 mL). The aqueous layer was separated and
extracted with two 10-mL portions of CH2Cl2, and the combined
organic phases were dried with Na2SO4, filtered and concentrated.
The crude reaction product was purified by flash chromatography
on silica gel to give the pure alkylated aziridines as colourless oils
and about 15Ϫ20% of self-condensation product.
CDCl3): δ ϭ 7.27Ϫ7.45 (m, 5 H), 4.13Ϫ4.31 (m, 2 H), 3.75 (dd,
J ϭ 9.8, 7.7 Hz, 1 H), 3.60 (dd, J ϭ 9.8, 4.8 Hz, 1 H), 3.36 (s, 3 H),
2.74 (dd, J ϭ 7.7, 4.8 Hz, 1 H), 2.49 (dd, J ϭ 6.5, 3.3 Hz, 1 H),
2.08 (d, J ϭ 3.3 Hz, 1 H), 1.52 (d, J ϭ 6.5 Hz, 1 H), 1.32 (t, J ϭ
7.2 Hz, 3 H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 171.0, 139.7,
128.5, 127.8, 77.9, 73.7, 61.1, 59.3, 39.5, 31.7, 14.4. Ϫ HRMS calcd.
for C14H20NO3: 250.1443, found 250.1441.
Aziridine 3(2R): Analytical TLC on silica gel, 95:5 CH2Cl2/cyclo-
hexane, Rf ϭ 0.42. Ϫ [α]D ϭ ϩ22 (c ϭ 0.95, CH2Cl2). Ϫ IR (neat):
1
2981 and 1743 cmϪ1. Ϫ MS: 250 [M ϩ 1]. Ϫ H NMR (300 MHz,
CDCl3): δ ϭ 7.24Ϫ7.43 (m, 5 H), 4.16 (q, J ϭ 7.3 Hz, 2 H), 3.76
(dd, J ϭ 9.8, 8.0 Hz, 1 H), 3.56 (dd, J ϭ 9.8, 4.4 Hz, 1 H), 3.37 (s,
3 H), 2.77 (dd, J ϭ 8.0, 4.4 Hz, 1 H), 2.44 (d, J ϭ 3.2 Hz, 1 H),
2.07 (d, J ϭ 6.6 Hz, 1 H), 1.99 (dd, J ϭ 6.6, 3.2 Hz, 1 H), 1.22 (t,
J ϭ 7.3 Hz, 3 H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 171.0, 139.8,
128.5, 127.7, 127.4, 78.2, 73.6, 61.1, 59.2, 36.5, 35.1, 14.3.
Aziridine 8a(2R): Analytical TLC on silica gel, 90:10 CH2Cl2/cyclo-
hexane, Rf ϭ 0.43. Ϫ [α]D ϭ Ϫ100 (c ϭ 1.0, CHCl3). Ϫ IR (neat):
2976, 2927 and 1712 cmϪ1. Ϫ MS: 350 [M ϩ 1]. Ϫ 1H NMR
(300 MHz, CDCl3): δ ϭ 7.35Ϫ7.20 (m, 5 H), 3.87 (dd, J ϭ 7.5,
Aziridine 4(2S): Analytical TLC on silica gel, 95:5 CH2Cl2/cyclo-
hexane, Rf ϭ 0.40. Ϫ [α]D ϭ Ϫ90 (c ϭ 1.42, CHCl3). Ϫ IR (neat): 4.7 Hz, 1 H), 3.72 (dd, J ϭ 9.8, 7.5 Hz, 1 H), 3.52 (dd, J ϭ 9.8,
1
2978 and 1738 cmϪ1. Ϫ MS: 248 [M ϩ 1]. Ϫ H NMR (300 MHz, 4.7 Hz, 1 H), 3.36 (s, 3 H), 2.35 (d, J ϭ 1.4 Hz, 1 H), 2.12 (d, J ϭ
CDCl3): δ ϭ 7.24Ϫ7.45 (m, 5 H), 2.50 (q, J ϭ 6.5 Hz, 1 H), 2.09
1.4 Hz, 1 H), 1.23 (s, 9 H), Ϫ0.04 (s, 9 H). Ϫ 13C NMR (75 MHz,
2592
Eur. J. Org. Chem. 2001, 2589Ϫ2594

Chiral Nonracemic tert-Butyl Aziridinecarboxylate Anions
FULL PAPER
CDCl3): δ ϭ 170.4, 141.2, 128.3, 127.9, 127.3, 81.1, 79.0, 64.3, 59.1, Aziridine 8b(2R): Analytical TLC on silica gel, 90:10 cyclohexane/
38.6, 33.3, 28.0, Ϫ1.5. Ϫ HRMS calcd. for C19H32NO3Si: 350.2151, EtOAc, Rf ϭ 0.24. Ϫ [α]D ϭ ϩ1.5 (c ϭ 0.8, CHCl3). Ϫ IR (neat):
found 350.2158.
2978, 2930, and 1720 cmϪ1. Ϫ MS: 292 [M ϩ 1]. Ratio of
invertomers: 1:1. Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 7.48Ϫ7.20
(m, 10 H), 3.84 (t, J ϭ 6.3 Hz, 1 H), 3.73 (dd, J ϭ 9.3, 7.7 Hz, 1
H), 3.60Ϫ3.46 (m, 3 H), 3.35 (s, 3 H), 3.34Ϫ3.30 (m, 1 H), 3.29 (s,
3 H), 2.53 (s, 1 H), 1.98 (s, 1 H), 1.72 (s, 1 H), 1.69 (s, 1 H), 1.53
(s, 9 H), 1.44 (s, 12 H), 1.18 (s, 3 H). Ϫ 13C NMR (75 MHz,
CDCl3): δ ϭ 171.9, 169.9, 141.2, 141.1, 128.3, 128.2, 128.0, 127.4,
127.2, 81.3, 80.7, 79.1, 77.8, 66.6, 63.1, 59.1, 42.8, 40.4, 38.8, 28.2,
Aziridine 8b(2S): Analytical TLC on silica gel, 95:5 CH2Cl2/cyclo-
hexane, Rf ϭ 0.24. Ϫ [α]D ϭ Ϫ111 (c ϭ 1.0, CHCl3). Ϫ IR (neat):
2977, 2930 and 1717 cmϪ1. Ϫ MS: 292 [M ϩ 1]. Ϫ 1H NMR
(300 MHz, CDCl3): δ ϭ 7.38Ϫ7.17 (m, 5 H), 3.83 (dd, J ϭ 7.5,
4.5 Hz, 1 H), 3.64 (dd, J ϭ 9.8, 7.5 Hz, 1 H), 3.54 (dd, J ϭ 9.8,
4.5 Hz, 1 H), 3.35 (s, 3 H), 2.41 (s, 1 H), 2.08 (s, 1 H), 1.40 (s, 3
H), 1.10 (s, 9 H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 169.5, 141.0,
128.1, 127.6, 127.1, 81.0, 79.1, 64.9, 59.2, 42.2, 39.3, 27.6, 20.9. Ϫ
HRMS calcd. for C17H26NO3: 292.1913, found 292.1932.
1
28.0, 21.3, 12.3. Ϫ H NMR (300 MHz, [D6]DMSO, 110 °C) δ ϭ
7.42Ϫ7.20 (m, 5 H), 3.60Ϫ3.40 (m, 3 H), 3.25 (s, 3 H), 2.12 (s, 1
H), 1.70 (s, 1 H), 1.45 (s, 9 H), 1.23 (s, 3 H). Ϫ HRMS calcd. for
C17H26NO3: 292.1913, found 292.1896.
Aziridine 8c(2S): Analytical TLC on silica gel, CH2Cl2, Rf ϭ 0.31.
Ϫ [α]D ϭ Ϫ86 (c ϭ 1.0, CHCl3). Ϫ IR (neat): 2979, 2929, and
Aziridine 8c(2R): Analytical TLC on silica gel, CH2Cl2, Rf ϭ 0.30.
Ϫ [α]D ϭ Ϫ41 (c ϭ 0.8, CHCl3). Ϫ IR (neat): 2978, 2926, and
1720 cmϪ1. Ϫ MS: 318 [M ϩ 1]. Ratio of invertomers: 4:1 (M for
major and m for minor). Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ
7.45Ϫ7.22 (m, 5HM ϩ 5Hm), 5.98Ϫ5.83 (m, 1HM), 5.58Ϫ5.53
(m, 1Hm), 5.10 (bd, J ϭ 17.8 Hz, 1HM), 5.04 (bd, J ϭ 10.8 Hz,
1HM), 4.98 (bd, J ϭ 16.1 Hz, 1Hm), 4.93 (bd, J ϭ 9.3 Hz, 1Hm),
3.75 (dd, J ϭ 8.1, 6.4 Hz, 1HM), 3.70 (m, 1Hm), 3.55Ϫ3.50 (m,
2HM ϩ 1Hm), 3.35 (m, 4Hm), 3.28 (s, 3HM), 2.72 (dd, J ϭ 14.6,
7.3 Hz, 1HM), 2.70 (s, 1Hm), 2.47 (dd, J ϭ 13.8, 7.4 Hz, 1Hm),
2.23 (dd, J ϭ 14.6, 6.4 Hz, 1HM), 2.00 (m, 1Hm), 1.98 (s, 1HM),
1.75 (s, 1Hm), 1.73 (s, 1HM), 1.52 (s, 9HM), 1.52 (s, 9Hm). Ϫ 13C
NMR (75 MHz, CDCl3): δ ϭ 169.1, 141.2 (M), 140.7 (m), 134.9
(M), 134.6 (m), 128.4, 128.1, 127.5, 117.0 (m), 116.7 (M), 81.6 (M),
80.9 (m), 79.1 (m), 77.9 (M), 66.9 (m), 63.3 (M), 59.1, 46.2, 39.5
1718 cmϪ1. Ϫ MS: 318 [M ϩ 1]. Ϫ H NMR (300 MHz, CDCl3):
1
δ ϭ 7.38Ϫ7.18 (m, 5 H), 5.83Ϫ5.70 (m, 1 H), 5.06 (dd, J ϭ 19.0,
1.4 Hz, 1 H), 5.02 (d, J ϭ 10.6 Hz, 1 H), 3.75 (dd, J ϭ 7.2, 4.3 Hz,
1 H), 3.63 (dd, J ϭ 9.7, 7.2 Hz, 1 H), 3.53 (dd, J ϭ 9.7, 4.3 Hz, 1
H), 3.45 (s, 3 H), 2.91 (dd, J ϭ 14.6, 7.1 Hz, 1 H), 2.41 (s, 1 H),
2.12 (s, 1 H), 2.08 (dd, J ϭ 14.6, 6.3 Hz, 1 H), 1.10 (s, 9 H). Ϫ
13C NMR (75 MHz, CDCl3): δ ϭ 168.5, 140.7, 134.6, 128.0, 127.7,
127.2, 117.0, 81.3, 79.0, 64.8, 59.2, 43.0, 39.9, 39.2, 27.6. Ϫ HRMS
calcd. for C19H28NO3: 318.2069, found 318.2066.
Aziridine 8d(2S): Analytical TLC on silica gel, 80:20 cyclohexane/
EtOAc, Rf ϭ 0.38. Ϫ [α]D ϭ Ϫ54 (c ϭ 1.1, CHCl3). Ϫ IR (neat):
2978, 2929 and 1732 cmϪ1. Ϫ MS: 392 [M ϩ 1]. Ϫ 1H NMR
(300 MHz, CDCl3): δ ϭ 7.38Ϫ7.17 (m, 5 H), 3.84 (dd, J ϭ 7.3,
4.4 Hz, 1 H), 3.63 (dd, J ϭ 9.8, 7.3 Hz, 1 H), 3.54 (dd, J ϭ 9.8,
4.4 Hz, 1 H), 3.36 (s, 3 H), 3.27 (d, J ϭ 17.0, 1 H), 2.58 (s, 1 H),
2.24 (s, 1 H), 2.12 (d, J ϭ 17.0, 1 H), 1.44 (s, 9 H), 1.08 (s, 9 H). Ϫ
13C NMR (75 MHz, CDCl3): δ ϭ 170.4, 167.8, 140.6, 128.1, 127.6,
127.2, 81.5, 80.6, 78.8, 64.5, 59.2, 41.4, 40.9, 40.3, 28.2, 27.5. Ϫ
HRMS calcd. for C22H34NO5: 392.2437, found 392.2430.
1
(M), 38.5, 37.2 (M), 31.2 (m), 29.8 (m), 28.2 (M), 28.0 (m). Ϫ H
NMR (300 MHz, [D6]DMSO, 110 °C): δ ϭ 7.40Ϫ7.22 (m, 5 H),
5.79 (ddt, J ϭ 17.2, 10.3, 6.7 Hz, 1 H), 5.08 (ddd, J ϭ 17.3, 3.5,
1.5 Hz, 1 H), 5.01 (ddd, J ϭ 10.3, 3.5, 1.5 Hz, 1 H), 3.60 (t, J ϭ
5.7 Hz, 1 H), 3.52 (dd, J ϭ 9.1, 5.8 Hz, 1 H), 3.50 (dd, J ϭ 9.1,
5.6 Hz, 1 H), 3.23 (s, 3 H), 2.54 (dd, J ϭ 14.7, 7.0 Hz, 1 H), 2.22
(ddt, J ϭ 14.7, 6.7, 1.5 Hz, 1 H), 2.06 (s, 1 H), 1.76 (s, 1 H), 1.49 (s,
9 H). Ϫ HRMS calcd. for C19H28NO3:318.2069, found 318.2070.
Aziridine 8e(2S): Analytical TLC on silica gel, 90:10 cyclohexane/
EtOAc, Rf ϭ 0.26. Ϫ [α]D ϭ Ϫ117 (c ϭ 0.8, CHCl3). Ϫ IR (neat):
2979, 2930, and 1718 cmϪ1. Ϫ MS: 368 [M ϩ 1]. Ϫ 1H NMR
(300 MHz, CDCl3): δ ϭ 7.42Ϫ7.12 (m, 10 H), 3.73Ϫ3.53 (m, 4 H),
3.37 (s, 3 H), 2.61 (d, J ϭ 14.8 Hz, 1 H), 2.55 (s, 1 H), 2.34 (s, 1
H), 0.93 (s, 9 H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 168.1, 140.7,
138.7, 129.0, 128.1, 127.7, 127.2, 126.3, 81.4, 79.0, 65.1, 59.2, 44.5,
40.6, 40.5, 27.4. Ϫ HRMS calcd. for C23H30NO3: 368.2226, found
368.2224. Ϫ For compounds from the functionalisation of aziridine
2(2R), the NMR spectra show two invertomers in different ratios
depending on which electrophile is used. Both invertomers are de-
Aziridine 8d(2R): Analytical TLC on silica gel, 80:20 cyclohexane/
EtOAc, Rf ϭ 0.50. Ϫ [α]D ϭ Ϫ38 (c ϭ 1.65, CHCl3). Ϫ IR (neat):
1727 cmϪ1. Ϫ MS: 392 [M ϩ 1]. Ϫ Only one invertomer in CDCl3.
Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 7.43Ϫ7.20 (m, 5 H), 3.84 (dd,
J ϭ 6.9, 5.7 Hz, 1 H), 3.56Ϫ3.46 (m, 1 H), 3.38Ϫ3.34 (m, 1 H),
3.29 (s, 3 H), 3.22 (d, J ϭ 16.9 Hz, 1 H), 2.20 (d, J ϭ 16.9 Hz, 1
H), 2.15 (s, 1 H), 1.87 (s, 1 H), 1.52 (s, 9 H), 1.46 (s, 9 H). Ϫ
13C NMR (75 MHz, CDCl3): δ ϭ 170.5, 168.5, 140.8, 128.4, 128.0,
127.5, 81.7, 80.5, 77.8, 62.6, 59.1, 43.4, 41.9, 37.5, 28.2, 28.1. Ϫ Two
1
1
scribed (NMR in CDCl3) and their H NMR spectra are given at
110 °C in deuterated DMSO (at this temperature, only one series
of signals is observed).
invertomers in [D6]DMSO at room temp. Ϫ H NMR (300 MHz,
[D6]DMSO, 110 °C): δ ϭ 7.40Ϫ7.22 (m, 5 H), 3.63 (t, J ϭ 6.0 Hz,
1 H), 3.56 (dd, J ϭ 9.6, 6.1 Hz, 1 H), 3.49 (dd, J ϭ 9.6, 5.8 Hz, 1
H), 3.25 (s, 3 H), 2.78 (d, J ϭ 16.5 Hz, 1 H), 2.28 (d, J ϭ 16.5 Hz,
1 H), 2.17 (s, 1 H), 1.87 (s, 1 H), 1.48 (s, 9 H), 1.42 (s, 9 H). Ϫ
HRMS calcd. for C22H34NO5:392.2437, found 392.2430.
Aziridine 8a(2S): For this compound, diastereomers could not be
separated. Analytical TLC on silica gel, 90:10 cyclohexane/EtOAc,
Rf ϭ 0.55. Ϫ IR (neat): 2977, 2929, and 1715 cmϪ1. Ϫ MS: 350
[M ϩ 1]. Ϫ Ratio of invertomers: 7:1; only major diastereomer is Self-Condensation Product 11(2S,2ЈR): Analytical TLC on silica
described. Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 7.47Ϫ7.20 (m, 5
gel, 95:5 CH2Cl2/cyclohexane, Rf ϭ 0.22. Ϫ [α]D ϭ Ϫ20 (c ϭ 1.0,
H), 3.74 (t, J ϭ 6.3 Hz, 1 H), 3.54Ϫ3.44 (m, 2 H), 3.31 (s, 3Hm), CHCl3). Ϫ IR (neat): 2927, 1732, and 1720 cmϪ1. Ϫ MS: 481 [M
3.23 (s, 3 H), 1.92 (s, 1 H), 1.76 (s, 1 H), 1.53 (s, 9 H), 1.47 (s, 9Hm), ϩ 1]. Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 7.42Ϫ7.24 (m, 8 H),
0.12 (s, 9 H), Ϫ0.14 (s, 9Hm). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ
7.09 (dd, J ϭ 5.8, 2.1 Hz, 2 H), 3.95 (dd, J ϭ 9.3, 3.3 Hz, 1 H), 3.77
170.5, 142.0, 128.3, 128.1, 127.4, 81.3, 78.1, 63.6, 58.9, 37.3, 35.6, (dd, J ϭ 9.6, 8.1 Hz, 1 H), 3.57 (dd, J ϭ 9.6, 4.4 Hz, 1 H), 3.37 (s,
28.3, Ϫ1.3. Ϫ 1H NMR (300 MHz, [D6] DMSO, 110 °C): δ ϭ
7.40Ϫ7.20 (m, 5 H), 3.65Ϫ3.45 (m, 3 H), 3.19 (s, 3 H), 1.94 (s, 1
H), 1.83 (s, 1 H), 1.51 (s, 9 H), 0.09 (s, 9 H). Ϫ HRMS calcd. for
C19H32NO3Si: 350.2151, found 350.2148.
3 H), 3.15 (s, 3 H), 3.13 (dd, J ϭ 9.5, 3.3 Hz, 1 H), 2.94 (dd, J ϭ
6.5, 3.3 Hz, 1 H), 2.91Ϫ2.80 (m, 2 H), 2.52 (d, J ϭ 3.3 Hz, 1 H),
2.16 (d, J ϭ 6.5 Hz, 1 H), 2.07 (d, J ϭ 1.0 Hz, 1 H), 1.94 (d, J ϭ
1.0 Hz, 1 H), 1.48 (s, 9 H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ
Eur. J. Org. Chem. 2001, 2589Ϫ2594
2593

V. Alezra, M. Bonin, L. Micouin, C. Policar, H.-P. Husson
FULL PAPER
[8]
I. Böhm, H.-U. Reissig, J. Am. Chem. Soc. 1982, 104,
1735Ϫ1737.
D. Seebach, R. Häner, Chem. Lett. 1987, 49Ϫ52.
R. Häner, B. Olano, D. Seebach, Helv. Chim. Acta 1987, 70,
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D. Seebach, A. R. Sting, M. Hoffman, Angew. Chem. Int. Ed.
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200.8, 165.8, 139.9, 139.5, 128.4, 128.2, 127.9, 127.5, 82.8, 78.4,
77.7, 74.4, 62.0, 59.1, 58.3, 51.8, 40.1, 38.8, 36.6, 28.0.
[9]
[10]
(S)-α-Benzylserine (10): [α]D ϭ Ϫ16 (c ϭ 1.1, H2O). Ϫ MS: 196 [M
ϩ 1]. Ϫ 1H NMR (300 MHz, D2O): δ ϭ 7.26Ϫ7.17 (m, 3 H),
7.11Ϫ7.05 (m, 2 H), 3.86 (d, J ϭ 12.1 Hz, 1 H), 3.60 (d, J ϭ
12.1 Hz, 1 H), 3.07 (d, J ϭ 14.2 Hz, 1 H), 2.79 (d, J ϭ 14.2 Hz, 1
H). Ϫ 13C NMR (75 MHz, D2O): δ ϭ 173.5, 133.5, 129.9, 129.0,
127.9, 66.9, 64.0, 37.8. Ϫ HRMS calcd. for C10H13NO3: 196.0974,
found 196.0961.
[11]
[12]
[13]
[14]
V. Alezra, M. Bonin, L. Micouin, H.-P. Husson, Tetrahedron
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K. Harada, I. Nakamura, J. Chem. Soc., Chem. Commun.
1978, 522Ϫ523.
Relative configuration of dimer 7 has been established by 1H
NMR: The chemical shifts of the aziridinyl proton signals are
typical for the (2R) or (2S) series.
Acknowledgments
This work was supported by the CNRS and MENRT. We thank
Dr. R. Gschwind (Marburg) for help in NMR determination of
nitrogen configuration and Prof. Meyer (Orsay) for help in IR ex-
periments.
[15]
[16]
M. Horikawa, T. Nakajima, Y. Ohfune, Synlett 1997, 253Ϫ254.
1
Relative configuration of dimer 11 has been established by H
NMR: The chemical shifts of the aziridinyl and tert-butyl ester
proton signals are typical for the (2R) or (2S) series.
E. J. Vedejs, J. T. Kendall, J. Am. Chem. Soc. 1997, 119,
6941Ϫ6942.
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Received November 30, 2000
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[O00617]
2594
Eur. J. Org. Chem. 2001, 2589Ϫ2594