An efficient synthesis of 2,3-aziridino-γ-lactones from azetidin-2-ones

Article abstract of DOI:10.1055/s-2005-872263

An efficient synthesis of enantiopure 2,3-aziridino-γ-lactones from azetidin-2-ones is described. Acid-catalyzed tandem intramolecular azetidinone ring opening followed by aziridine ring formation via elimination of a mesylate group is the key step in thi

Full text of DOI:10.1055/s-2005-872263

2370
LETTER
An Efficient Synthesis of 2,3-Aziridino-g-lactones from Azetidin-2-ones
2
, 3-Aziridino-
g
-lac
j
tones
f
a
rom Azetid
y
in-2-ones kumar S. Kale, Abdul Rakeeb A. S. Deshmukh*
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune – 411 008, India
Fax +91(20)25893153; E-mail: aras.deshmukh@ncl.res.in
Received 4 July 2005
For the last couple of years we have engaged in using aze-
tidin-2-ones as synthons8 for the synthesis of biologically
useful organic molecules. As a part of this research
program we herein report an efficient synthesis of
Abstract: An efficient synthesis of enantiopure 2,3-aziridino-g-lac-
tones from azetidin-2-ones is described. Acid-catalyzed tandem in-
tramolecular azetidinone ring opening followed by aziridine ring
formation via elimination of a mesylate group is the key step in this
synthesis. 2,3-Aziridino-g-lactones are important precursors for enantiopure 2,3-aziridino-g-lactones from 3-benzyl-
biologically important glutamic acid derivatives.
oxyazetidin-2-ones 1.
Key words: azetidin-2-ones, aziridines, lactones, glutamic acid
2,3-Aziridino-g-lactones are very important intermediates
in the synthesis of biologically useful 3,4-dihydroxy
glutamic acids, analogues of L-glutamic acid, an impor-
The b-lactam skeleton, apart from composing the partial
structure of a variety of b-lactam antibiotics,1–3 has been
recognized as a useful building block in the synthesis of a
variety of pharmaceutically useful products.4 The strain
energy associated with the four-membered azetidin-2-one
ring makes it susceptible to nucleophilic ring cleavage.
The selective bond cleavage of the strained ring coupled
with the possibility of further transformations make this
molecule a powerful building block.5 There have been
many efforts made in exploring new aspects of b-lactam
chemistry using enantiomerically pure b-lactams as versa-
tile intermediates for the synthesis of heterocyclic non b-
lactam structures,6 aromatic b-amino acids, and their de-
rivatives,7 oligopeptides,4c labelled peptides, and aze-
tidines, which can be further converted to polyamines,
polyamino alcohols, amino sugars, and polyamino
ethers.4a
tant excitatory neurotransmitter of the central nervous
system.9 The regioselective nucleophilic opening of the
aziridine ring also gives a variety of useful products10 in-
cluding a-amino acids, such as polyoxamic acid10a and b-
amino acids.10c The regioselectivity of the ring cleavage is
mainly controlled by the hardness and softness of the
nucleophile.10b There are few reports11 on the synthesis of
2,3-aziridino-g-lactone analogues; some of these are
multi-step reactions (12–14 steps)11c,e that give low over-
all yield of the desired product. We wish to report a short
and efficient synthesis of 2,3-aziridino-g-lactones from
optically pure 3-benzyloxy-b-lactams. The key step in this
synthesis is the selective intramolecular nucleophilic b-
lactam ring opening followed by aziridine ring formation
via elimination of the mesylate group (Scheme 1).
The starting 3-benzyloxy-azetidin-2-one (1a) was ob-
tained in good yield12 and enantiopurity by Staudinger’s
ketene-imine cycloaddition reaction. The ketene was
generated in situ from benzyloxyacetyl chloride using tri-
ethylamine and the imine was prepared by the reaction of
D-glyceraldehyde acetonide with benzylamine. The ben-
zyl group was removed by transfer hydrogenation13 using
ammonium formate and Pd/C (10%) to provide the corre-
sponding 3-hydroxy-b-lactam 2a in very good yield. It
was then converted to its meslylate 3a by its reaction with
methanesulfonyl chloride in the presence of triethyl-
amine.12b The removal of the acetonide group was
achieved by refluxing 3a in THF–H2O with a catalytic
amount of PTSA giving dihydroxy-b-lactam 4a in excel-
lent yield. Dihydroxy-b-lactam 4a was refluxed in metha-
nolic HCl (20%) for 18 hours (monitored by TLC). The
extractive work-up with ethyl acetate gave 2,3-aziridino-
g-lactone 5a as a thick oil. The IR spectrum of 5a showed
a strong absorption band at 1780 cm–1 for the g-lactone
carbonyl group and the 1H NMR spectrum did not show a
singlet for the methyl group indicating the elimination of
the mesylate group during the aziridine ring formation.
One of the aziridine ring protons appeared as a doublet at
2.80 ppm (J = 4.5 Hz) and the other proton appeared as a
doublet of doublet at 3.14 ppm (J = 3.1 and 4.5 Hz). The
O
O
O
H
H
N
H
H
N
H
H
N
H
H
H
MsO
BnO
HO
O
O
O
a
b
O
R
O
R
O
R
1a–c
2a–c
3a–c
1a, R = Bn
2a, R = Bn, 90%
3a, R = Bn, 91%
1b, R = PMP
1c, R = p-Tolyl
2b, R = PMP, 92%
2c, R = p-Tolyl, 91%
3b, R = PMP, 88%
3c, R = p-Tolyl, 91%
R
OH
H
H
H
N
H
MsO
H
OH
c
d
H
OH
N
O
O
O
R
4a–c
5a–c
4a, R = Bn, 95%
5a, R = Bn, 86%
4b, R = PMP, 96%
4c, R = p-Tolyl, 96%
5b, R = PMP, 82%
5c, R = p-Tolyl, 82%
Scheme 1 Reagents and conditions: a) 10% Pd/C, HCOONH4,
MeOH, reflux, 0.5 h; b) MsCl, Et3N, CH2Cl2, –10 °C, r.t., 2 h; c) PTSA,
THF–H2O, reflux, 12–24 h; d) HCl–MeOH (20%), reflux, 18–24 h.
SYNLETT 2005, No. 15, pp 2370–2372
1
9
.0
9
.2
0
0
5
Advanced online publication: 03.08.2005
DOI: 10.1055/s-2005-872263; Art ID: G17605ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
2,3-Aziridino-g-lactones from Azetidin-2-ones
2371
Table 1 Synthesis of 2,3-Aziridino-g-lactones 5a–c and 8a–c
Entry.
Compound
Ra
Reaction time (h) Mp (°C)
Yield (%)b
[a]D30 (CHCl3)
1
2
3
4
5
6
5a
5b
5c
8a
8b
8c
Bn
20
24
18
8
Thick oil
Thick oil
Thick oil
Thick oil
92–94
86
82
82
80
81
83
–40.0 (c 1.5)
+1.0 (c 1.75)
+16.0 (c 0.5)
–1.6 (c 0.9)
+18.0 (c 1.0)
+60.0 (c 1.5)
PMP
p-Tolyl
Bn
PMP
p-Tolyl
15
17
95–96
a PMP = 4-Methoxyphenyl.
b Isolated yields.
R
N
OH
O
H
H
N
H
H
N
H
H
N
MsO
MsO
MsO
OH
H
H
b
OH
a
c
H
O
R
O
R
R
O
O
O
4a–c
6a–c
7a–c
8a–c
4a, R = Bn
6a, R = Bn, 80%
7a, R = Bn, 82%
8a, R = Bn, 80%
4b, R = PMP
4c, R = p-Tolyl
6b, R = PMP, 85%
6c, R = p-Tolyl, 90%
7b, R = PMP, 84%
7c, R = p-Tolyl, 80%
8b, R = PMP, 81%
8c, R = p-Tolyl, 83%
Scheme 2 Reagents and conditions: a) NaIO4 supported on silica gel, MeOH, r.t., 3.5 h; b) NaBH4, MeOH–THF, r.t., 3 h; c) HCl–MeOH
(20%), reflux, 8–17 h.
benzyl protons appeared as two doublets at 3.35 and 3.82 Acknowledgment
ppm (J = 13.0 Hz). Spectral data clearly revealed the for-
The authors thank DST for financial support and CSIR for research
fellowships to ASK.
mation of 2,3-aziridino-g-lactone 5a via one-pot azetidi-
none ring opening followed by aziridine ring formation.14
Other 2,3-aziridino-g-lactones 5b,c were also prepared
References
(Table 1) from 1b,c following the above synthetic pro-
cedure (Scheme 1) and were characterized by spectral
analyses.
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The formation of 2,3-aziridino-g-lactone was further con-
firmed by the synthesis of aziridino-g-lactone 8a and
comparing its spectral data with the reported racemic
compound (Scheme 2).11b Oxidative cleavage, by silica
gel supported sodium metaperiodate,15 of dihydroxy-b-
lactam 4a gave 4-formyl-b-lactam 6a, which on reduction
with sodium borohydride gave hydroxy-b-lactam 7a in
good yield. This was further subjected to intramolecular
nucleophilic ring cleavage. Compound 7a was refluxed
with methanolic HCl for eight hours to afford 2,3-aziridi-
no-g-lactone 8a in very good yield. The IR and NMR
spectral data16 of 8a was found to be exactly similar with
that reported for the racemic compound.11b This confirms
the formation of aziridino-g-lactones via tandem nucleo-
philic azetidinone ring opening and aziridine ring forma-
tion. Other aziridino-g-lactones 8b,c were also prepared
in good yields (Table 1, Scheme 2).
In conclusion, we have demonstrated an efficient synthe-
sis of 2,3-aziridino-g-lactones using azetidin-2-ones as
synthons. One-pot nucleophilic azetidinone ring opening
followed by the formation of an aziridine ring is the key
step in this synthesis. The generality of this synthetic pro-
cedure was established by the preparation of 2,3-aziridi-
no-g-lactones 5a–c and 8a–c.
Synlett 2005, No. 15, 2370–2372 © Thieme Stuttgart · New York

2372
A. S. Kale, A. R. A. S. Deshmukh
LETTER
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was dissolved in methanolic HCl (20%, 10 mL) and the
reaction mixture was refluxed for 20 h. After the reaction
was over (TLC), MeOH was removed under reduced
pressure and sat. NaHCO3 was added to the residue. It was
then extracted with EtOAc (3 × 20 mL) and the combined
organic extract was washed with brine (10 mL). It was then
dried over anhyd Na2SO4 and the solvent was removed under
reduced pressure to provide a thick oil, which was quickly
purified by flash column chromatography (acetone–
petroleum ether, 4:1) to furnish 5a (0.300 g, 86%) as a thick
oil.
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(d) Krishnaswamy, D.; Govande, V. V.; Deshmukh, A. R. A.
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[a]D30 –40 (c 1.5, CHCl3); IR (CHCl3): 3417, 1780 cm–1; 1H
NMR (CDCl3, 200 MHz): d = 7.34–7.38 (m, 5 H), 4.46–4.53
(m, 1 H), 3.78–3.94 (m, 2 H), 3.82 (d, J = 13.0 Hz, 1 H), 3.35
(d, J = 13.0 Hz, 1 H), 3.14 (dd, J = 3.1, 4.5 Hz, 1 H), 2.80 (d,
J = 4.5 Hz, 1 H), 2.26 (br s, 1 H); 13C NMR (50.32 MHz,
CDCl3): d =171.8, 136.8, 128.6, 127.8, 127.7, 79.3, 61.6,
60.8, 42.8, 40.0; MS (70 eV): m/z = 242 (M+); Anal. Calcd
for C12H13NO3: C, 65.73; H, 5.98; N, 6.40. Found: C, 65.50;
H, 6.01; N, 6.24.
(15) Zhong, Y.-L.; Shing, T. K. M. J. Org. Chem. 1997, 62, 2622.
(16) (1S,5R)-6-Benzyl-3-oxa-6-azabicyclo[3.1.0]hexan-2-one
(8a) was synthesized from 3-hydroxymethyl-azetidin-2-one
(7a) following the procedure described for compound 5a.14
8a: Thick oil, 80%; [a]D30 –1.6 (c 0.9, CHCl3); IR (CHCl3):
1774 cm–1; 1H NMR (CDCl3, 200 MHz): d = 7.30–7.40 (m,
5 H), 4.34 (d, J = 9.8 Hz, 1 H), 4.21 (dd, J = 9.8, 3.1 Hz, 1
H), 3.74 (d, J = 13.5 Hz, 1 H), 3.47 (d, J = 13.5 Hz, 1 H),
2.96 (dd, J = 4.5, 3.1 Hz, 1 H), 2.72 (d, J = 4.5 Hz, 1 H); 13
C
NMR (50.32 MHz, CDCl3): d = 172.3, 137.0, 128.6, 127.8,
127.7, 69.5, 61.1, 42.1, 39.7; MS (70 eV): m/z = 190 (M+);
Anal. Calcd for C11H11NO2: C, 69.81; H, 5.86; N, 7.40.
Found: C, 69.62; H, 5.43; N, 7.19.
Synlett 2005, No. 15, 2370–2372 © Thieme Stuttgart · New York