Synthesis of aziridine-2-carboxylates via conjugate addition of an amine to 2-(5H)-furanon-3-yl methanesulfonate: Application to the preparation of α-amino-β-hydroxy-γ-butyrolactone

Article abstract of DOI:10.1016/S0040-4039(00)00335-X

Conjugate addition of benzylamine to 2-(5H)-furanon-3-yl methanesulfonate in methanol afforded a 7:1 mixture of the trans and cis methyl N-benzyl-2-hydroxymethylaziridine-2-carboxylates 7 and 8, respectively. Treatment of 7 with benzyl alcohol in the presence of BF₃·OEt₂ then furnished, after hydrogenolysis, rac-cis α-amino-β- hydroxy-γ-butyrolactone (1). (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00335-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3061–3064
Synthesis of aziridine-2-carboxylates via conjugate addition of an
amine to 2-(5H)-furanon-3-yl methanesulfonate: application to
the preparation of α-amino-β-hydroxy-γ-butyrolactone
Carole de Saint-Fuscien and Robert H. Dodd ∗
Institut de Chimie des Substances Naturelles, Centre National de la Recherche Scientifique, 91198 Gif-sur-Yvette Cedex,
France
Received 23 January 2000; accepted 9 February 2000
Abstract
Conjugate addition of benzylamine to 2-(5H)-furanon-3-yl methanesulfonate in methanol afforded a 7:1 mixture
of the trans and cis methyl N-benzyl-2-hydroxymethylaziridine-2-carboxylates 7 and 8, respectively. Treatment
of 7 with benzyl alcohol in the presence of BF3·OEt2 then furnished, after hydrogenolysis, rac–cis α-amino-β-
hydroxy-γ-butyrolactone (1). © 2000 Elsevier Science Ltd. All rights reserved.
α-Amino-β-hydroxy-γ-butyrolactone (1) represents a valuable building block in organic synthesis by
virtue of the high concentration of varied functional groups present on a relatively small framework. The
cis derivative of 1 has, for example, been used for the preparation of complex β-lactam antibiotics1,2 and
both the cis and trans forms are precursors of the biologically important class of α-amino-β-hydroxy
acids.3
Several methods for the synthesis of racemic or chiral 1 have been described. These include: via
ammonolysis of epoxysuccinic acid,1 by treatment of α-bromo-β-hydroxy-γ-butyrolactone with sodium
azide,3 by a Strecker reaction starting from D-glyceraldehyde acetonide,4 by selective bromination of L-
threonic acid2 and by a chemo-enzymatic route starting from glycine.5 Most of these procedures require
multiple steps, or produce 1 in modest overall yields.
It occurred to us that an efficient route to 1 could be based on the conjugate addition of an amine to an
unsaturated furanone substrate bearing a leaving group at the α-position (e.g. 2, X=leaving group) to give
an intermediate of type 3 (Scheme 1). Intramolecular displacement of the leaving group by the amine
would then give rise to the aziridino-γ-lactone 4. As work from our laboratory has previously shown,
related aziridino-γ-lactones (prepared from carbohydrate derivatives) are opened at the β-position by
alcohols in the presence of a Lewis acid.6–9 With a substrate such as 4 this would furnish the desired
∗
Corresponding author. Fax: 33-1-69 07 72 47; e-mail: robert.dodd@icsn.cnrs-gif.fr (R. H. Dodd)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00335-X
tetl 16615

3062
trans α-amino-β-alkoxy-γ-butyrolactone 5 which could, presumably, be transformed into 1 by a choice
of appropriate R and R0 groups.
Scheme 1.
While conjugate additions of amines to 2-(5H)-furanones (i.e. 2, X=H) have been well
documented,10–18 examples of such reactions on substrates having a leaving group at the α-position
are less well known. Farina and co-workers19 have examined the reaction of benzylamine with the
α-bromo-γ-methoxy derivative of 2 in CCl4. Conjugate addition was observed, but the reaction was
incomplete and the products (a mixture of diastereomers) were too unstable to allow full characterization.
Use of the α-chloro analogue led, in contrast, essentially to the product of 1,2-attack. There was no
evidence, in either case, of formation of aziridine derivatives.
In view of this apparent instability of the α-halo-γ-lactone derivatives, we decided to pursue our
objectives using the α-O-mesylate 2 (X=OSO2CH3). The latter was prepared by treatment of commercial
D-erythronic γ-lactone 6 with excess methanesulfonyl chloride in pyridine and dichloromethane at
0°C for 20 h (Scheme 2).20 Conjugate addition of benzylamine was then effected using conditions
analogous to those described by Collis and Perlmutter11 for reaction of this same nucleophile with a
simple butenolide (i.e. having no leaving group at the α-position). Thus, compound 2 (X=OSO2CH3), in
methanol and THF (added to allow its complete solubilization) containing 2 equivalents of triethylamine
(to neutralize any methanesulfonic acid released during the reaction), was treated with 1 equivalent
of benzylamine for 7 h at 0°C. Two principal products were formed which were easily separated
by column chromatography on silica gel (ethyl acetate:heptane, 2:3). Proton NMR and mass spectral
analysis of these two compounds showed that both were methyl N-benzylaziridine-2-carboxylates.
The major product (rac-7, 42%) was attributed the trans configuration based on the H2–H3 coupling
constant of 2.4 Hz while the minor product (rac-8, 6%), having a larger H2–H3 coupling constant
(J=6.7 Hz), corresponded to the cis isomer.21–23 While small amounts of the benzylcarboxamides
corresponding to 7 and 8 were also isolated from the reaction mixture (overall yield <5%), there was
no evidence for the formation of the anticipated aziridine-γ-lactone species of type 4. Nevertheless,
reaction of the trans aziridine-2-carboxylate 7 with benzyl alcohol at reflux in chloroform in the
presence of 2 equivalents of boron trifluoride etherate then provided the rac–cis α-benzylamino-β-
benzyloxy-γ-lactone 9 in 50% yield (non-optimized).6,24 Finally, hydrogenolytic removal of the two
benzyl groups of 9 in methanol–water containing HCl gave rac–cis α-amino-β-hydroxy-γ-butyrolactone
(1) as the hydrochloride salt, whose physical and spectroscopic characteristics corresponded to literature
values.3,4,25
Formation of the trans aziridine 7 as the major product of conjugate addition of benzylamine to
butyrolactone 2 (X=OSO2CH3) can be rationalized in terms of selective facial protonation of the initially
formed enol I (Scheme 3). Based on a model proposed by Cram and Elhafez26 and exploited by Cromwell
et al.,27 protonation of the α-position during the course of tautomerization of the enol would be expected
to occur from the least hindered side of the ring; that is, on the side opposite the benzylamine group,
to give the cis α-methanesulfonyloxy-β-amino-butyrolactone II (pathway A). The latter then reacts
with methanol to afford ester III which assumes a conformation IV allowing SN2 displacement of the
mesylate by the amine. This process thus provides aziridine 7 as the major product. It is interesting

3063
Scheme 2.
to note that no conjugate addition products were observed in the absence of methanol.28 A similarly
high stereoselectivity of conjugate addition of benzylamine to acrylates in the presence of methanol has
recently been reported.29
Scheme 3.
The two-step reaction process described herein consists, in fact, of five transformations (conjugate
addition, lactone opening, aziridine formation, aziridine opening, relactonization) which allows efficient
inversion of the nitrogen and oxygen functionalities on the α- and β-positions of the γ-butyrolactone
(A→B). Furthermore, while the expected aziridino-γ-lactone 4 was not obtained, the aziridine-2-
carboxylates 7 and 8, produced instead by this novel methodology, represent highly interesting synthetic
tools.30
This model study presented to test the feasibility of the approach does not permit preparation of chirally
pure products. However, because it has been shown that the presence of a substituent at the γ-position of
γ-butyrolactones allows almost complete stereocontrol of conjugate addition of amines,11,14–17 extension

3064
of our methodology to such substrates should, in principle, lead to enantiomerically pure products. This
possibility is currently under study.
Acknowledgements
We thank MENRT for a fellowship (C.S.F.) and Dr. P. Dauban for discussions and many helpful
suggestions.
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