Cu-promoted single-pot intramolecular esterification of C-3 functionalized azetidin-2-one: An efficient diastereoselective access to azido-/amino-aza- lactones

Article abstract of DOI:10.1016/j.tetlet.2014.05.016

A facile, single pot diastereoselective access to seven and eight membered aza-heterocycles was developed by using β-lactam-synthon approach. The developed protocol does not involve the typical intricacies viz. the use of expensive transition metal catalysts and high boiling solvents, associated with the convenient protocols.

Full text of DOI:10.1016/j.tetlet.2014.05.016

Accepted Manuscript
Cu-promoted single-pot intramolecular esterification of C-3 functionalized aze-
tidin-2-one: An efficient diastereoselective access to azido-/amino-aza-lactones
Kewal Kumar, Sumit Kumar, Tejinder Singh, Amit Anand, Vipan Kumar
PII:
S0040-4039(14)00794-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.05.016
TETL 44607
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
6 March 2014
5 May 2014
7 May 2014
Please cite this article as: Kumar, K., Kumar, S., Singh, T., Anand, A., Kumar, V., Cu-promoted single-pot
intramolecular esterification of C-3 functionalized azetidin-2-one: An efficient diastereoselective access to azido-/
amino-aza-lactones, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.05.016
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Cu-promoted single-pot intramolecular esterification of
C-3 functionalized azetidin-2-one: An efficient
diastereoselective access to azido-/amino-aza-lactones
Kewal Kumar, Sumit Kumar, Tejinder Singh, Amit Anand, Vipan Kumar*
TBDMSO
n
O
O
O
O
O
H
N3
H
NH2
N
CuSO4.5H2O
Zn/NH4Cl
n
n
EtOH, rt, 2h
°
,1h
MeOH, 60 C
N3
H
H
R
N
H
N
H
H H
R
R
n=1-2

1
Tetrahedron Letters
jo u rn al h ome p ag e : w ww .e lsevier .com
Cu-promoted single-pot intramolecular esterification of C-3 functionalized
azetidin-2-one: An efficient diastereoselective access to azido-/amino-aza-
lactones
Kewal Kumar, Sumit Kumar, Tejinder Singh, Amit Anand, Vipan Kumar*
*Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, India
ARTICLE INFO
ABSTRACT
Article history:
Received
A facile, single pot diastereoselective access to seven and eight membered aza-heterocycles was
developed by using β-lactam-synthon approach. The developed protocol does not involve the
typical intricacies viz. the use of expensive transition metal catalysts and high boiling solvents,
associated with the convenient protocols.
Received in revised form
Accepted
Available online
Keywords:
Aza-lactones
Disteroselectivity
β-lactam synthon approach
Functionalized azetidin-2-ones
Intramolecular amidolysis
intermediates in the organic synthesis.22 β-lactam synthon
methodology is considered as a powerful armamentarium
available with the synthetic chemists as its application in the field
of synthesis and drug discovery is phenomenal. The approach has
been extensively used for the synthesis of oligopeptides,
enantiopure succinimides, 1,4-diazepanes, piperazines, non
protein aminoacids, peptidomimetics along with different sized
heterocycles of medicinal interest i.e. indolizidine alkaloids,
paclitaxel, docetaxel, taxoids, cryptophycins, lankacidins, etc.23
Medium sized ring lactones are considered as the
crucial structural motifs in naturally occurring bioactive
molecules.1,2 They have received special attention because of
their numerous applications such as drug candidates,3 catalysts4
and materials.5 Among the various activities exhibited by these
compounds, their potential as non-nucleoside HIV-1 reverse
transcriptase inhibitor,6 histamine receptor agonist,7 calcium
antagonists,8
antidepressants,9
analgesics,10
anxiolytic,11
antiserotoninergic and anticancer activity against breast cancer
cells is well established.12
In continuation of our interest in the synthesis of
diversely functionalized heterocycles via ring transformation of
C-3 functionalized β-lactams,24 the present work describes the
diastereoselective synthesis of seven and eight membered aza-
lactones via Cu-promoted intramolecular amidolysis of C-3
functionalized azetidin-2-ones. The synthetic methodology
involved an initial protection of the free hydroxyl group of 2-
Past few years have witnessed the development of a
numbers of synthetic protocols for macro-lactonization viz.
Corey-Nicolaou S-pyridyl ester lactonization,13 Mukaiyama
onium salt,14 Masamune thiol ester activation,15 Mitsunobu
alcohol activation,16 Shiina benzoic anhydride,17 Yamaguchi
mixed anhydride,18 and Keck-Steglich DCC/DMAP.HCl
activation19 methods. However these methods are invariably
associated with a number of drawbacks including long reaction
time, low to average yields, use of expensive transition metal
catalysts and high boiling solvents. Moreover, the synthesis of
medium-sized ring lactones is considered arduous because of the
unfavorable enthalpy and entropy considerations.20 Thus the
development of facile and efficient methodologies to
macrolactonization with readily available starting materials and
reagents remains a challenging task.
amino-1-ethanol or 3-amino-1-propanol
1
with tert-
butyldimethylsilyl chloride in the presence of imidazole with
subsequent treatment with trans-cinnamaldehyde to yield the
corresponding 1-azadienes 3. The synthesized 1-azadiene 3 was
then utilized in the synthesis of 3-azidoazetidin-2-ones 4 via well
established Staudinger reaction with azidoacetic acid in the
presence of p-toluenesulfonyl chloride and triethylamine.25
Sodium methoxide promoted ring amidolysis of β-lactam 4
resulted in the formation of equimolar diastereomeric mixture of
β-aminoesters 5 and 6 (Scheme 1).
β-lactams are evergreen bioactive molecules exhibiting
broad medicinal and pharmacological profiles,21 and as the key
The formation of the diastereomeric mixture may either
involve methoxide promoted amidolysis followed by base
induced isomerization (Path-B) or the amidolysis preceded by
isomerization (Path-A) as shown in Scheme 2. However, under
*Corresponding author. Tel.: +91 8146300146.
E-mail address: vipan_org@yahoo.com (V. Kumar).

2
Tetrahedron Letters
the employed reaction conditions, epimerization might be more
facilitated in the case of β-amino esters (Path-B) than β-lactams
because of the inherent ring strain of the β-lactam nucleus. 26
The diastereomeric mixture was utilized as such for further
synthetic endeavours viz. an initial de-protection using
CuSO4.5H2O27 to result in the isolation of an equimolar mixture
of corresponding 2-azido-3-(2-hydroxyalkylamino)-methyl esters
7 and 8 followed by refluxing in toluene in the presence of
catalytic amount of p-toluene sulfonic acid to yield substituted
trans and cis 6-azido-5-styryl-1,4-oxazepan-7-one 9 and 10 (n=1)
respectively as shown in Scheme 1. The careful chromatographic
separation of the diastereomeric mixture enabled the isolation
and characterization of 9 and 10 with the help of spectral data
and analytical evidences. The cis- and trans- stereochemistry to
these products was assigned on the basis of coupling constant J =
4.8 Hz for cis- and J = 9.6 Hz for trans-isomer respectively. The
equimolar mixture of 9 and 10 was further reduced to yield the
corresponding amines 11 and 12 via Zn/NH4Cl protocol.
TBDMSO
TBDMSO
n
n
O
N
NH
O
NaOMe
MeOH
H
R
OMe
R
N3
H
H
H
N3
4
6
NaOMe
MeOH
NaOMe
MeOH
Path-A
Path-B
TBDMSO
TBDMSO
n
n
O
NH
O
N
NaOMe
MeOH
H
R
OMe
R
N3
H
H
H
N3
4A
5
Scheme 2: Plausible mechanism for the formation of β-
aminoesters 5 and 6
O
OH
R
H
R
N
O
TBDMSCl, Imidazole,
Dry DCM, rt, 30 min.
H2N
OTBDMS
H2N
TBDMS
n
n
Anhydrous Na2SO4
Dry DCM, rt, 15 min.
n
H
1
96% for n=2
91% for n=3
3
91% for n=2
93% for n=3
2
OH
p-TSCl, Et3N,
Dry DCM
N3
O
TBDMSO
TBDMSO
n
TBDMSO
HO
R
HO
n
n
n
n
O
.
CuSO4 5H2O
N
NaOMe, MeOH
rt, 12-15 h
NH
O
NH
O
NH
O
NH
O
H
+
+
H
H
°
H
,1h
MeOH, 60
C
R
R
OMe
R
N3
R
OMe
OMe
H H
OMe
H
H
H
H
N3
N3
N3
N3
65-88%
68-75%
46-59%
4
6
8
5
7
p-TsOH, toluene
reflux, 4 h
O
O
O
O
O
O
O
O
H
NH2
H
Zn/NH4Cl
EtOH, rt, 2h
H
H
n
+
n
NH2
+
n
n
N3
N3
H
H
H
R
H
R
N
H
11
N
H
12
N
H
10
N
H
9
R
R
Entry
n
1
2
1
2
1
2
1
2
R
%age yield (9+10)
Entry
n
1
2
1
2
1
2
1
2
R
%age yield (11+12)
9a+10a
9b+10b
9c+10c
9d+10d
9e+10e
9f+10f
C6H5
C6H5
79
86
77
80
83
74
81
87
11a+12a
C6H5
C6H5
91
89
94
87
93
90
88
86
11b+12b
11c+12c
11d+12d
11e+12e
11f+12f
4-CH3-C6H4
4-CH3-C6H4
4-Cl-C6H4
4-CH3-C6H4
4-CH3-C6H4
4-Cl-C6H4
4-Cl-C6H4
CH=CH-C6H5
CH=CH-C6H5
4-Cl-C6H4
CH=CH-C6H5
CH=CH-C6H5
9g+10g
9g+10g
11g+12g
11g+12g
Scheme 1: Step-wise synthesis of diastereomeric mixture of 9, 10 and 11, 12

3
It was felt that the diastereoselectivity in the above sequence of
reactions could be achieved by introducing a nucleophilic centre
prior to the amidolysis of β-lactam ring. This might result in
preference of intramolecular cyclization over epimerization
leading to the diastereoselective formation of [1,4]oxazepan-7-
ones (n=1) and [1,5]oxazocan-2-ones (n=2). Thus, the treatment
of racemic 3-azido-β-lactams 4 with CuSO4.5H2O in methanol at
60 °C, interestingly resulted in the single pot diastereoselective
synthesis of substituted cis [1,4]oxazepan-7-ones (n=1) and
[1,5]oxazocan-2-ones (n=2) respectively, which were further
reduced into corresponding amines 12 via Zn/NH4Cl reduction
protocol in quantitative yields (Scheme 3).28 Further, the absence
of even traces of corresponding azetidin-2-ones 13 in the reaction
mixture as evidenced by its crude 1H NMR spectrum is
suggestive of the fact that the relaxation of ring strain is the
driving force for the described transformation.
TBDMSO
HO
n
O
O
n
O
OH
n
O
O
N
O
CuSO4.5H2O
°
H
H
N
N
O
n
N3
Zn/NH4Cl
n
,1h
MeOH, 60 C
NH2
H
R
N3
H
EtOH, rt, 2h
H H
N
H
10
R
N3
N
H
R
N3
H H
R
H H
R
12
4
13
14
Entry n
R
%age yield
Entry n
R
%age yield
10a
1
2
1
2
1
2
1
2
C6H5
87
82
88
78
80
85
89
84
12a
12b
12c
12d
12e
12f
1
2
1
2
1
2
1
2
C6H5
C6H5
94
91
96
93
96
94
96
91
10b
10c
10d
10e
10f
C6H5
4-CH3-C6H4
4-CH3-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-CH3-C6H4
4-CH3-C6H4
4-Cl-C6H4
4-Cl-C6H4
10g
10g
CH=CH-C6H5
CH=CH-C6H5
12g
12g
CH=CH-C6H5
CH=CH-C6H5
Scheme 3: Diastereoselective synthesis of 10 and 12
In conclusion, the present manuscript entails a highly facile,
single-pot diastereoselective synthesis of synthetically arduous
seven and eight membered aza-lactones via intramolecular ring
amidolysis of azetidin-2-ones. Since, the described protocol does
not involve the use of expensive transition metal catalysts or high
boiling solvents; the approach does not suffer from the typical
drawbacks associated with the conventional routes.
Acknowledgments
References and notes
1.
(a) Blunt, J. B.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.;
Prinsep, M. R. Nat. Prod. Rep. 2006, 23, 26; (b) Nubbemeyer, U. Top.
Curr. Chem. 2001, 216, 125; (c) Maier, M. E. Angew. Chem. Int. Ed.
2000, 39, 2073; (d) Lindström, U. M.; Somfai, P. Chem. Eur. J. 2001, 7,
94; (e) Bieraügel, H.; Jansen, T. P.; Schoemaker, H. E.; Hiemstra, H.;
van Maarseveen, J. H. Org. Lett. 2002, 4, 2673.
13. Corey, E. J.; Ulrich, P.; Fitzpatrick, J. M. J. Am. Chem. Soc. 1976, 98,
222.
14. (a) Mukaiyama, T. Angew. Chem. Int. Ed. Engl. 1979, 18, 707; (b)
Bartlett, P. A.; Green, F. R., III. J. Am. Chem. Soc. 1978, 100, 4858.
15. (a) Masamune, S.; Hirama, M.; Mori, S.; Ali, S. A.; Garvey, D. S. J.
Am. Chem. Soc. 1981, 103, 1568; (b) Masamune, S.; Hayase, Y.;
Schilling, W.; Chan, W. K.; Bates, G. S. J. Am. Chem. Soc. 1977, 99,
6756.
2.
3.
(a) Shiina, I. Chem. Rev. 2007, 107, 239; (b) Nicolaou, K. C.;
Vourloumis, D.; Winssinger, N.; Baran, P. Angew. Chem. Int. Ed. 2000,
39, 44.
16. (a) Moreau, X.; Campagne, J. M. J. Org. Chem. 2003, 68, 5346; (b)
Dvorak, C. A.; Schmitz, W. D.; Poon, D. J.; Pryde, D. C.; Lawson, J. P.;
Amos, R. A.; Meyers, A. I. Angew. Chem., Int. Ed. 2000, 39, 1664.
17. Shiina, I.; Kubota, M.; Oshiumi, H.; Hashizume, M. J. Org. Chem.
2004, 69, 1822.
Murray, P. J.; Kranz, M.; Ladlow, M.; Taylor, S.; Berst, F.; Holmes, A.
B.; Keavey, K. N.; Jaxa-Chamiec, A.; Seale, P. W.; Stead, P.; Upton, R.
J.; Croft, S. L.; Clegg, W.; Elsegood, M. R. Bioorg. Med. Chem. Lett.
2001, 11, 773.
4.
(a) Sanchez-Quesada, J.; Ghadiri, M. R.; Bayley, H.; Braha, O. J. Am.
Chem. Soc. 2000, 122, 11757; (b) Bong, D. T.; Clark, T. D.; Granja, J.
R.; Ghadiri, M. R. Angew. Chem. Int. Ed. 2001, 40, 988.
18. (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989; (b) Inanaga, J.; Katsuki, T.; Takimoto,
S.; Ouchida, S.; Inoue, K.; Nakano, A.; Okukado, N.; Yamaguchi, M.
Chem. Lett. 1979, 1021.
5.
6.
7.
Jarvo, E. R.; Miller, S. J. Tetrahedron 2002, 58, 2481.
Xing, X. L.; Wu, J. L.; Luo, J. L.; Dai, W. Synlett 2006, 2099.
Smits, R. A.; Lim, H. D.; Stegink, B.; Bakker, R. A.; de Esch, I. J. P.;
Leurs, R. J. Med. Chem. 2006, 49, 4512.
19. Keck, G. E.; Boden, E. P.; Wiley, M. R. J. Org. Chem. 1989, 54, 896.
20. (a) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95; (b) Yet,
L. Chem. Rev. 2000, 100, 2963.
8.
9.
Li, R.; Farmer, P. S.; Wang, J.; Boyd, R. J.; Cameron, T. S.; Quilliam,
M. A.; Walter, J. A.; Howlett, S. E. Drug Des. Discovery 1995, 12, 337.
Nagarajan, K.; David, J.; Kulkarni, Y. S.; Hendi, S. B.; Shenoy, S. J.;
Upadhyaya, P. Eur. J. Med. Chem. Chim. Ther. 1986, 21, 21.
21. (a) Alcaide, B.; Almendros, P.; Aragoncillo, C. Curr. Opin. Drug.
Discov. Dev. 2010, 13, 685; (b) qysek, R.; Katarzyna Borsuk, K.;
Furman, B.; Ka1uza, Z.; Kazimierski, A.; Chmielewski, M. Curr. Med.
Chem. 2004, 11, 1813; (c) Deshmukh, A. R. A. S.; Bhawal, B. M.;
Krishnaswamy, D.; Govande, V. V.; Shinkre, B. A.; Jayanthi, A. Curr.
Med. Chem. 2004, 11, 1889. (d) Sperka, T.; Pitlik, J.; Bagossia, P.;
Tozsera, J. Bioorg. Med. Chem. Lett. 2005, 15, 3086; (e) Kumar, A.;
Rajput, C. S. Eur. J. Med. Chem. 2009, 44, 83; (f) Cainelli, G.; Galletti,
P.; Garbisa, S.; Giacomini, D.; Sartorb, L.; Quintavalla, A. Bioorg. Med.
Chem. 2005, 13, 6120.
10. (a) Hallinan, E. A.; Hagen, T. J.; Tsymbalov, S.; Stapelfeld, A.; Savage,
M. A. Bioorg. Med. Chem. 2001, 9, 1; (b) Wu, J.; Jiang, Y.; Dai, W. M.
Synlett 2009, 1162.
11. Van der Burg, W. J. Chem. Abstr. 1974, 81, 3986; DE2347727.
12. Diaz-Gavilan, M.; Rodritimeguez-Serrano, F.; Gomez-Vidal, J. A.;
Marchal, J. A.; Aranega, A.; Gallo, M. A.; Espinosa, A.; Campos, J. M.
Tetrahedron 2004, 60, 11547.
22. (a) Martinek, T. A.; Fulop, F. Chem. Soc. Rev. 2012, 41, 687; (b)
D’hooghe, M.; Dekeukeleire, S.; Leemans, E.; De Kimpe, N. Pure Appl.

4
Tetrahedron
Chem. 2010, 82, 1749; (c) Dekeukeleire, S.; D’hooghe, M.; De
Kimpe, N. J. Org. Chem. 2009, 74, 1644; (d) Mollet, K.; D’hooghe, M.;
De Kimpe, N. J. Org. Chem. 2011, 76, 264; (e) D’hooghe, M.; Mollet,
K.; Dekeukeleire, S.; De Kimpe, N. Org. Biomol. Chem. 2010, 8, 607;
(f) Fodor, L.; Csomos, P.; Csampai, A.; Sohar, P. Tetrahedron 2012, 68,
851.
23. (a) Alcaide, B.; Almendros, P.; Cabrero, G.; Ruiz, M. P. Chem.
Commun. 2007, 4788; (b) Kamath, A.; Ojima, I. Tetrahedron 2012, 68,
10640; (c) Dekeukeleire, S.; D’hooghe, M.; Vanwalleghem, M.;
Brabandt, W. V.; De Kimpe, N. Tetrahedron 2012, 68, 10827.
24. (a) Mehra, V.; Kumar, V. Tetrahedron Lett. 2014, 55, 845; (b) Mehra,
V.; Kumar, V. Tetrahedron Lett. 2013, 54, 6041; (c) Mehra, V.; Kumar,
V. Tetrahedron 2013, 69, 3857; (d) Mehra, V.; Singh, P.; Kumar, V.
Tetrahedron 2012, 68, 8395; (d) Mehra, V.; Singh, P.; Manhas, N.;
Kumar, V. 2014, Synlett, doi: 10.1055/s-0033-1341049.
25. Singh, P.; Sachdeva, S.; Raj, R.; Kumar, V.; Mahajan, M. P.; Nasser, S.;
Vivas, L.; Gut, J.; Rosenthal, P. J.; Feng, T. S.; Chibale, K. Bioorg.
Med. Chem. Lett. 2011, 21, 4561.
26. Singh, P.; Mehra, V.; Anand, A.; Kumar, V. Mahajan, M.P.
Tetrahedron Lett. 2011, 52, 5060.
27. González-Calderón, D.; Benítez-Puebla, L. J.; González-González, C.
A.; Assad-Hernández, S.; Fuentes-Benítez, A.; Cuevas-Yáñez, E.;
Corona-Becerril, D.; González-Romero, C. Tetrahedron Lett. 2013, 54,
5130.
28. Typical procedure for the diastereoselective synthesis of
azido[1,4]oxazepan-7-ones and azido[1,5]oxazocan-2-ones 10: To a
stirred solution of 4 (1 mmol) in methanol (10 mL) was added
CuSO4.5H2O (1.5 mmol) and the reaction mixture was heated at 60 °C
for 1 hour. The progress of the reaction was monitored using TLC and
on completion, the reaction mixture was filtered, concentrated under
reduced pressure with subsequent addition of water (20 mL) and
extraction with ethyl acetate (2 x 20 mL). The combined organic layers
were dried using anhydrous Na2SO4 and concentrated under vacuo to
obtain a light yellow solid. The crude product, thus obtained was
recrystallized using hexane:ethyl acetate (8:2) mixture.
6(SR)-azido-5(RS)-styryl-[1,4]oxazepan-7-one (10a):
Light yellow
1
solid; Yield 87%; mp 79-80 °C; IR (KBr) = 1732 cm-1; H NMR (400
MHz, CDCl3): δ 3.16-3.22 (m, 1H, -NH-, exchangeable with D2O),
3.40-3.46 (m, 2H, --CH2-), 3.76-3.80 (m, 2H, -CH2-), 4.50 (dd, J = 4.80,
8.76 Hz, 1H, H2), 4.90 (d, J = 4.64 Hz, 1H, H1), 6.18 (dd, J = 8.92,
15.84 Hz, 1H, H3), 6.77 (d, J = 15.84 Hz, 1H, H4), 7.28-7.39 (m, 3H, -
ArH), 7.45-7.46 (m, 2H, -ArH); 13C NMR (100 MHz, CDCl3): 45.0,
59.6, 60.6, 67.3, 122.0, 126.9, 128.7, 128.8, 135.4, 137.8, 165.2; HRMS
(ESI-micrOTOF-QII): Calcd for C13H14N4O2: 258.1117 [M]+ found
258.1112; Anal Calcd for C13H14N4O2: C, 60.45; H, 5.46; N, 21.69;
Found C, 60.31; H, 5.49; N, 21.63.
Typical procedure for the diastereoselective synthesis of
amino[1,4]oxazepan-7-ones and amino[1,5]oxazocan-2-ones 12: To the
stirred solution of 10 (1 mmol) in EtOH:H2O (9:1) mixture at room
temperature was added NH4Cl (2.5 mmol) followed by the gradual
addition of Zn powder (1.5 mmol). The reaction mixture was stirred for 2
hours at room temperature and the progress was monitored using TLC.
On completion, the reaction mixture was filtered and the pH was adjusted
to 8 by addition of ammonia solution. The filtrate was washed with brine
(2 x 25 mL) and subsequently extracted with ethyl acetate (2 x 20 mL).
The combined organic layers were dried over anhydrous Na2SO4,
concentrated under vacuo to yield the corresponding amine which was
recrystallized by using hexane:ethyl acetate (7:3) mixture.
6(SR)-amino-5(RS)-styryl-[1,4]oxazepan-7-one (12a): Off white solid;
1
Yield 94%; mp 134-135 °C; IR (KBr) = 1728 cm-1; H NMR (300 MHz,
CDCl3): δ 1.78 (brs, 2H, -NH2, exchangeable with D2O), 3.22-3.37 (m,
2H, -CH2-), 3.82-3.85 (m, 2H, -CH2-), 4.36-4.42 (m, 2H, H1+H2), 6.17
(dd, J = 7.80, 15.90 Hz, 1H, H3), 6.69 (d, J = 15.90 Hz, 1H, H4), 7.29
7.43 (m, 6H, 5ArH+1NH); 13C NMR (75 MHz, CDCl3): 45.9, 59.8, 61.8,
63.0, 123.2, 126.6, 128.4, 128.7, 135.6, 136.5, 165.5; HRMS (ESI-
micrOTOF-QII): Calcd for C13H16N2O2: 232.1212 [M]+ found 232.1204;
Anal Calcd for C13H16N2O2: C, 67.22; H, 6.94; N, 12.06; Found C, 67.41;
H, 6.88; N, 12.17.

5
ꢀ Cu-promoted intramolecular amidolysis of C-3
functionalized azetidin-2-ones
ꢀ Diastereoselective access to seven and eight
membered aza-lactones
ꢀ Developed approach does not suffer from the
drawbacks of conventional routes