A new straightforward synthesis of 2,3-aziridino-γ-lactones

Article abstract of DOI:10.1016/S0040-4039(00)01071-6

A concise synthesis of 2,3-aziridino-γ-lactones starting from commercially available α,β-dihydroxy-γ-lactones is described. The strategy involves a Michael-type addition of benzylamine onto a key 2-(5H)-furanon-3-yl trifluoromethanesulfonate, followed by in situ cyclization to the aziridine without lactone-ring-opening. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01071-6

Tetrahedron Letters 41 (2000) 6393±6397
A new straightforward synthesis of 2,3-aziridino-g-lactones
Carole de Saint-Fuscien, Aurelie Tarrade, Philippe Dauban and Robert H. Dodd*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette, France
Received 24 May 2000; accepted 23 June 2000
Abstract
A concise synthesis of 2,3-aziridino-g-lactones starting from commercially available a,b-dihydroxy-g-lactones
is described. The strategy involves a Michael-type addition of benzylamine onto a key 2-(5H)-furanon-3-yl
tri¯uoromethanesulfonate, followed by in situ cyclization to the aziridine without lactone-ring-opening.
# 2000 Elsevier Science Ltd. All rights reserved.
Keywords: aziridine; furanone; Michael-type addition; tri¯ate.
Aziridine chemistry still represents an area of intense investigation which has been reviewed
several times in the last ten years.1 This strained heterocycle has recently been incorporated in a
wide range of biologically active compounds (antitumor agents,2a,b cysteine protease2c or squalene
synthase inhibitors,2d fatty acids2e or pregnene derivatives,2f peptidomimetics2g i) and can be
found in the structure of several natural products (mitomycins and analogues,3a azinomycins3b).
Aziridines have also emerged as useful ligands in the ®eld of asymmetric synthesis.4 However,
most synthetic studies have been dedicated to the preparation of a plethora of target molecules
e.g. aza- and amino-sugar derivatives,5 alkaloid analogues,6 vicinal diamines,7 amino alcohols8
and, last but not least, substituted amino acids.9 They have also proved to be valuable
intermediates for the total synthesis of trunkamide,10a physostigmine,10b (R)-(^)- and (S)-(+)-
dysidazirine,10c (^)-yohimbane,10d balanol,10e cephalotaxine,10f sphingosine,10g pancratistatin
10
and quisqualic acid.10i
In this general context, we have been engaged in the development of bicyclic aziridines,
h
e.g. 2,3-aziridino-g-lactone 1,11 which has recently culminated in the ®rst enantiospeci®c total
synthesis of one isomer of naturally occurring 3,4-dihydroxy-l-glutamic acid 2 (Scheme 1).11g
Although ecient, the preparation of compounds of type 1 from carbohydrate derivatives is
rather long, hampering further studies related to the biological activity of such disubstituted
amino acids.12 A shorter pathway was clearly needed and it was with this intention in mind that
we decided to explore another strategy based on a tandem Michael-type addition±cyclization. We
* Corresponding author. Tel: 01 69 82 45 94; fax: 01 69 07 72 47; e-mail: robert.dodd@icsn.cnrs-gif.fr
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01071-6

6394
Scheme 1.
have recently reported the application of this procedure to the 2-(5H)-furanon-3-yl methane-
sulfonate 3, using benzylamine as the nucleophile in the presence of methanol (Scheme 2).13
However, only a mixture of cis- and trans-aziridine 2-carboxylates 4 was obtained.
Scheme 2.
In order to facilitate formation of the aziridine ring, and perhaps prevent opening of the
lactone ring, we decided to replace the methanesulfonate by a better leaving group. We thus
turned our attention to the tri¯ate derivative 6 which was obtained by treatment of d-erythronic
g-lactone 5 with tri¯ic anhydride and pyridine in dichloromethane (Scheme 3).14 The resulting
faintly colored liquid was puri®ed by ¯ash chromatography on silica gel and could be stored at
4ꢀC for several weeks without notable degradation.
Scheme 3.
Application of the general conditions of Scheme 2 to compound 6 then led to the desired 2,3-
aziridino-g-lactone 7, albeit in rather low yield (25%, entry 1, Table 1), in addition to the trans
and cis- aziridine-2-carboxylates 4 obtained as by-products in 18 and 8% yield, respectively. The
1
structure of 7 was evident from its H-NMR spectrum where the protons of the aziridine ring
appeared down®eld at 2.72 and 2.96 ppm, compared to those of the aziridine 2-carboxylates 4 at
2.62 and 2.79 ppm for the trans isomer, and at 2.23 and 2.38 ppm for the cis isomer. There was no
signal corresponding to a methyl ester or a benzyl amide, indicating that the lactone ring was
intact. Moreover, the IR spectrum of 7 showed an absorption band for the carbonyl function at
1776 cm^1 characteristic of the 2,3-aziridino-g-lactones.11
After considerable experimentation, it was found that the presence of triethylamine was
detrimental to the yield and that the use of 2 equiv. benzylamine was optimal. At this stage, we
presumed that use of a more hindered alcohol as the co-solvent would reduce the formation of
lactone ring-opened products. Therefore, replacement of methanol by isopropanol allowed
isolation of 7 in a still modest but more acceptable yield of 38% (entry 2). Since unidenti®ed

6395
Table 1
side-products were still formed; we decided next to replace the protic solvent by polar aprotic
solvents. Use of a mixture of THF and HMPA in a 9:1 ratio hence led to a slightly better yield of
43% (entry 3). While acetonitrile alone led to essentially the same result (entry 4), nitromethane
was less ecient (entry 5). Surprisingly, when the reaction was run in DMSO, only decomposition
of the starting tri¯ate was observed (entry 6). Finally, the best result was obtained using DMF
(entry 7), which allowed isolation of compound 7 in 55% yield. DMF was also shown by Feringa to
be the solvent of choice for Michael-type additions of amines to 5-substituted-2(5H)-furanone.15
With this methodology in hand, we then decided to turn our attention to chiral substrates, in
particular to the 5-O-trityl derivative 9, easily accessible from d-ribonolactone 8 in two steps
(Scheme 4). Treatment of compound 9 with 1.5 equiv. benzylamine in DMF then a€orded
aziridine-g-lactone 10 in 60% yield.16 This reaction needed to be carefully monitored by TLC since
prolonged reaction times (>15 min) led to concomitant lactone ring-opening by excess benzylamine,
the latter being necessary to optimize the yield. The 13C and 1H NMR spectra of 10 clearly indicated
formation of a single diastereoisomer corresponding to Michael-type addition of benzylamine to
the face opposite to that of the bulky substituent at the C-5 position. This stereochemistry was
deduced from the 1H NMR spectrum, where no coupling was observed between H-3 and H-4, as
previously noticed for the 2,3-aziridino-g-lactones in the ribo series.11a,e Such diastereoselective
control has been previously observed in the literature in analogous compounds.17
Scheme 4.

6396
In conclusion, a straightforward and ecient synthesis of 2,3-aziridino-g-lactones has been
developed based on the Michael-type addition of an amine to a 2(5H)-furanon-3-yl
tri¯uoromethanesulfonate. Only two and three steps are needed starting from commercially
available d-erythronic-g-lactone 5 and d-ribonolactone 8, respectively. We are currently
investigating application of this methodology to the synthesis of natural products and/or
biologically active compounds.
Acknowledgements
We thank MENRT for a fellowship (C.S.F.).
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