Practical preparation and substitution of configurationally stable aziridinyl ester anions

Article abstract of DOI:10.1016/S0040-4039(99)02156-5

Configurationally and chemically stable aziridine carboxylate anions have been generated. These intermediates are stable at -78°C for several hours and react with electrophiles with good to excellent retention of configuration. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02156-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 651–654
Practical preparation and substitution of configurationally stable
aziridinyl ester anions
Valérie Alezra, Martine Bonin, Laurent Micouin and Henri-Philippe Husson ∗
Laboratoire de Chimie Thérapeutique associé au CNRS et à l’Université René Descartes (UMR 8638), Faculté des Sciences
Pharmaceutiques et Biologiques, 4 Avenue de l’Observatoire, 75270 Paris cedex 06, France
Received 26 August 1999; accepted 16 November 1999
Abstract
Configurationally and chemically stable aziridine carboxylate anions have been generated. These intermediates
are stable at −78°C for several hours and react with electrophiles with good to excellent retention of configuration.
© 2000 Elsevier Science Ltd. All rights reserved.
Chiral non-racemic aziridines are known to be useful electrophilic synthetic intermediates, mainly
because of their regio- and stereoselective ring-opening reactions.1 However, very limited work on the
use of aziridinyl anions as configurationally stable nucleophilic species has so far been published, despite
their obvious potential for asymmetric synthesis.2 For example, practical generation and handling of
anionic aziridine-esters would be of particular interest for the elaboration of functionalized α- or β-
quaternary amino acid derivatives.3 This problem was studied by Seebach and co-workers, who reported
that all attempts to deprotonate an aziridine ester led to degradation and/or self-condensation of these
reactive species.4 However, these authors were able to prepare several aziridine thiolesters which could
be functionalized at a very low temperature (−100°C) with retention of configuration for compound 1
and moderate d.s. (33–60%) for its diastereomer 2 (Scheme 1). To our knowledge, no practical use of
this strategy for the elaboration of quaternary aziridine-esters has been reported since these pioneering
works, probably because of the low chemical and, in some cases, configurational stability of such reactive
species.
The practical preparation of ‘non-stabilized’ metalated aziridines was recently studied by Vedejs and
co-workers. They showed that these compounds could be obtained by direct lithiation after nitrogen
complexation with borane,2c or by a tin–lithium exchange.2b In the latter case, a beneficial role of a
neighboring methoxymethyl (MOM) group in this exchange was observed.
With respect to these results, and in continuation of our work on the use of (R)-phenylglycinol
as the source of chirality and nitrogen,5 we investigated the deprotonation and functionalization of
∗
Corresponding author. Tel: 33 (0)1 53 73 97 54; fax: 33 (0)1 43 29 14 03; e-mail: husson@pharmacie.univ-paris5.fr (H.-P.
Husson)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02156-5
tetl 16084

652
Scheme 1.
aziridine esters of type 3, with the expectation that the methoxyl group could improve the chemical
and configurational stability of the reactive species (Scheme 1).6
Several aziridine esters 4–6 were prepared, according to a reported procedure.7 All the diastereomers
could be separated by column chromatography (Scheme 2).
Scheme 2.
As expected, deprotonation of the compounds 4–6 proved to be troublesome. Among all the bases
tested (NaH, LiHMDS, KHMDS, t-BuLi, LDA) only LDA (in THF) appeared to be the appropriate
reagent for completion of deprotonation. Of the aziridine esters prepared, t-butyl ester 6 (2S) proved to
be a suitable substrate for our study (Table 1),8 whereas aziridines 4 and 5 bearing less hindered esters
led only to self-condensation.
Table 1

653
The t-butyl ester 6 (2S) could be deprotonated by LDA in THF and reacted with various halides
at −78°C. The use of DMPU as a cosolvent led to an improvement in chemical yields, but was not
essential, in contrast with previous observations on aziridine carbothioates anions.4 In all the cases only
one diastereomer could be detected by 1H and 13C NMR. Retention of configuration was demonstrated
by chemical correlation of aziridine 7e with (S)-α-benzylserine after ester hydrolysis, ring opening with
HClO4 and hydrogenolysis.9
We then turned our attention toward the functionalization of compound 6 (2R). Under the same
conditions (LDA, THF, −78°C), only self-condensation was observed. Since intramolecular stabiliza-
tion appeared to be ineffective with this compound, we tried to stabilize the highly reactive lithiated
intermediate by intermolecular chelation. The use of TMEDA (3 equiv.) as a cosolvent led to the allyl
compound 7c when using allyl bromide as electrophile, but in a moderate yield (39%) and only 88/12
d.r. In contrast, in a 5:1 mixture of DME:Et2O, aziridine 6 (2R) could be deprotonated and reacted with
halides in a moderate yield but with good to excellent retention of configuration (Table 2).10
Table 2
These results constitute a large improvement of the configurational stability observed in the analogous
thiolester series.11
In conclusion, we were able to generate configurationally and chemically stable aziridine carboxylate
anions. These intermediates are stable at −78°C for several hours and react with halides with good to
excellent retention of configuration. The origin of chemical and configurational stability of such species
is under investigation and will be reported in due course.
Acknowledgements
One of us (V.A.) thanks MENRT for a grant.
References
1. (a) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599–619. (b) Baldwin, J. E.; Farthing, C. N.; Russel, A. T.; Schofield,
C. J.; Spivey, A. C. Tetrahedron Lett. 1996, 37, 3761–3764.

654
2. (a) Satoh, T. Chem. Rev. 1996, 96, 3303–3325 and references cited therein. (b) Vedejs, E. J.; Moss, W. O. J. Am. Chem. Soc.
1993, 115, 1607–1608. (c) Vedejs, E. J.; Kendall, J. T. J. Am. Chem. Soc. 1997, 119, 6941–6942.
3. (a) Williams, R. M. Synthesis of Optically Active α-Amino Acids; Pergamon: Oxford, 1989. (b) Seebach, D.; Sting, A. R.;
Hoffmann, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 2708–2748. (c) Wirth, T. Angew. Chem., Int. Ed. Engl. 1997, 36,
225–227.
4. (a) Seebach, D.; Häner, R. Chem. Lett. 1987, 49–52. (b) Häner, R.; Olano, B.; Seebach, D. Helv. Chim. Acta 1987, 70,
1676–1691.
5. For recent studies, see: (a) Roussi, F.; Bonin, M.; Chiaroni, A.; Micouin, L.; Riche, C.; Husson, H.-P. Tetrahedron Lett. 1999,
40, 3727–3730. (b) Blanchet, J.; Bonin, M.; Chiaroni, A.; Micouin, L.; Riche, C.; Husson, H.-P. Tetrahedron Lett. 1999, 40,
2935–2938.
6. (a) Gawley, R. G.; Zhang, Q. Tetrahedron 1994, 50, 6077–6088. (b) Burchat, A. F.; Chong, J. M.; Park, S. B. Tetrahedron
Lett. 1993, 34, 51–54.
7. Harada, K.; Nakamura, I. J. Chem. Soc., Chem. Commun. 1978, 522–523.
8. Absolute configuration of 6 (2S) was assigned by chemical correlation of 6 (2R) with D-serine by ester hydrolysis, ring
opening with HClO4 and hydrogenolysis. [α]D=+7.7 (c=2.45, H2O) lit.: +7 (c=1, H2O) Watanabe, K. A.; Falco, E. A.; Fox,
J. J. J. Org. Chem. 1972, 37, 1198–1201.
9. [α]D=+16 (c=1.1, H2O) lit.: +16.4 (c=0.81, H2O) Horikawa, M.; Nakajima, T.; Ohfune, Y. Synlett 1997, 253–254.
10. Invertomers were noticed in 1H NMR spectra of the quaternary aziridines derived from compound 6 (2R). This phenomenon
helped us to evaluate inversion free energy for these compounds to be about 16–17 kcal/mol (T=333 K, DMSO) by classical
NMR experiments.
11. Typical procedures for alkylation of compound 6 (2S): With DMPU: To a solution of aziridine 6 (2S) (150 mg, 0.54 mmol)
in dry THF (10 mL) at −78°C under argon atmosphere was added LDA (1.5 M in cyclohexane, 722 µL, 1.08 mmol). After
1 h, the electrophile (1.62 mmol) and the DMPU (196 µL, 1.62 mmol) were consecutively added. The reaction mixture
was maintained at −78°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 portions of CH2Cl2, and the combined organic phases were dried over MgSO4,
filtered and concentrated. The crude reaction product was purified by flash chromatography on silica gel to give the pure
alkylated aziridines as colorless oils. Without DMPU: To a solution of aziridine 6 (2S) (140 mg, 0.50 mmol) in dry THF
(10 mL) at −78°C under argon atmosphere was added LDA (1.5 M in cyclohexane, 674 µL, 1.01 mmol) via cannula. After
1 h, the electrophile (1.52 mmol) was added. The reaction mixture was maintained at −78°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 over MgSO4, filtered and concentrated. The crude reaction product
was purified by flash chromatography on silica gel to give the pure alkylated aziridines as colorless oils.
Typical procedures for alkylation of compound 6 (2R): To a solution of aziridine 6 (2R) (140 mg, 0.50 mmol) in a mixture of
dry DME (5 mL) and Et2O (1 mL) at −78°C under argon atmosphere was added LDA (1.5 M 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 −78°C
for 2 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 over Na2SO4, filtered and concentrated. The
crude reaction product was purified by flash chromatography on silica gel to give the pure alkylated aziridines as colorless
oils and about 15–20% of self-condensation product.