An efficient synthesis of azetidine-2,3-diones from L-(+)-diethyl tartrate

Article abstract of DOI:10.1055/s-2007-985563

A convenient route to enantiopure azetidine-2,3-diones is described. The chiral ketene generated from commercially available L-(+)-diethyl tartrate on Staudinger cycloaddition with different imines gave spiro-β-lactams in good yields. These spiro-β-lactam

Full text of DOI:10.1055/s-2007-985563

2242
LETTER
An Efficient Synthesis of Azetidine-2,3-diones from L-(+)-Diethyl Tartrate
An
Efficient
S
i
ynthes
n
A
zetidin
a
e-2,3-dion
k
s
from
L
-(+)-Dieth
M
yl Tartrate . Chincholkar,a Vedavati G. Puranik,b Abdul Rakeeb A. S. Deshmukh*c
a
b
c
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411008, India
Centre for Materials Characterization, National Chemical Laboratory, Pune 411008, India
Emcure Pharmaceuticals Limited, ARC-H, P-2, I.T.-B.T. Park, Phase-II, M.I.D.C., Hinjwadi, Pune- 411057, India
Fax +91(20)39821445; E-mail: Abdulrakeeb.Deshmukh@emcure.co.in
Received 29 May 2007
synthesis.15 More recently, another elegant application of
azetidine-2,3-diones in peptide synthesis has been report-
ed using their reaction with primary amines.16
Abstract: A convenient route to enantiopure azetidine-2,3-diones
is described. The chiral ketene generated from commercially avail-
able L-(+)-diethyl tartrate on Staudinger cycloaddition with differ-
ent imines gave spiro-b-lactams in good yields. These spiro-b-
lactams were transformed into azetidine-2,3-diones in excellent
yields in a two-step process.
The most widely used method for the synthesis of azeti-
dine-2,3-diones is oxidation of 3-hydroxy b-lactams.17
However, besides this method few other methods are also
available in the literature.18–21 Most of the reports dealing
with the applications of enantiopure azetidine-2,3-
diones13–16 utilize the method of oxidation of correspond-
ing 3-hydroxy b-lactams. Interestingly these chiral 3-hy-
droxy b-lactams have been synthesized starting with
chiral imines. While this has proved to be a useful method,
difficulties can be encountered in some cases. Some ap-
plications of b-lactams demand presence of aryl groups at
N-1 and C-4 positions of the b-lactam.14f,22 In such cases
it becomes difficult to start with a chiral imine. Thus, a
method which provides enantiopure azetidine-2,3-diones
and simultaneously allows flexibility in the choice of sub-
stituents on the imine moiety is desired. Towards this end
we have devised a short route to enantiopure azetidine-
2,3-diones starting with L-(+)-diethyl tartrate.
Key words: stereoselective synthesis, lactams, imines, cycloaddi-
tion, spiro compounds
b-Lactams, being a part of most widely used antibiotics,1
are a familiar class of compounds in organic synthesis.
The resurgence of bacterial activity against traditional an-
tibiotics has inevitably led to the discovery of newer b-
lactam antibiotics with modified structures. Recent times
have witnessed an upsurge in the number of new varied
applications of b-lactams.2–11 Among these, the most im-
portant application that has outgrown most other applica-
tions is the use of b-lactams as a synthon for biologically
important molecules.12 One particularly important and
useful class of synthons are substituted azetidine-2,3-di-
ones. They have been shown to be promising building
blocks13 and precursors for highly functionalized b-
lactams14 including Sch-48461 and Sch-58235 which
display an important cholesterol absorption inhibitory
activity (Figure 1).
Commercially available L-(+)-diethyl tartrate was protect-
ed as an acetonide 2 following a reported procedure23
(Scheme 1). Selective hydrolysis of one of the ester
groups of 2 yielded mono acid in good yield, which was
subsequently converted into acid chloride 3 by refluxing
with oxalyl chloride in dichloromethane. Acid chloride 3
was used as a ketene precursor in Staudinger cycloaddi-
tion reaction, which reacted cleanly with imines 4a–c to
furnish a diastereomeric mixture of spiro-b-lactams 5a–c
Apart from synthesis of these functionalized b-lactams,
other applications involve synthesis of a-amino acid N-
carboxy anhydrides which have been used in peptide
3-allyl ß-lactams
3-alkyl/aryl
1
and 6a–c in about 60:40 ratio as indicated by the H
NMR.24 Both diastereomers displayed a strong band
around 1755 cm–1 in the IR spectrum indicating the pres-
ence of a b-lactam group. The only proton on the lactam
ring appeared as a singlet at d = 5.19 and d = 4.87 in the
major diastereomer 5a and the minor diastereomer 6a, re-
spectively, along with other signals from the tartrate moi-
ety. Absolute configurations at the newly generated chiral
centers were determined with the help of single crystal X-
ray analyses. Major diastereomer 5a on X-ray analysis25
(Figure 2) was found to have configuration 3S,4S. How-
ever, the minor isomer could not be obtained in crystalline
form.
ß-lactams,
Sch 48461
novel taxol
analogues
ref. 14a
ref. 14b
H
ref. 14f
O
O
R2
N
R1
ref. 14e
3-trimethyl
silyloxy
ß-lactams
ref. 14c
3-alkylidene
ref. 14d
ß-lactams
bicyclic ß-lactam
precursors
Figure 1 Applications of azetidine-2,3-diones in synthesis
Figure 3 depicts all the theoretically possible products of
Staudinger cycloaddition between the diethyl tartrate de-
rived ketene and imines. With the attack of imine possible
SYNLETT 2007, No. 14, pp 2242–2246
Advanced online publication: 24.07.2007
DOI: 10.1055/s-2007-985563; Art ID: G17507ST
© Georg Thieme Verlag Stuttgart · New York
0
3
.0
9
.2
0
0
7

LETTER
An Efficient Synthesis of Azetidine-2,3-diones from L-(+)-Diethyl Tartrate
2243
O
CO2Et
CO2Et
CO2Et
CO2Et
COCl
CO2Et
O
HO
HO
O
O
O
O
a
b
R1
N
H
CO2Et
O
H
H
R2
3
2
5a–c major
1
R2
H
CO2Et
O
R2
O
H
CO2Et
CO2Et
R1
N
O
O
c
COOEt
R1
N
R1
N
H
O
+
O
O
6a–c minor
O
O
H
H
H
R2
O
O
5a–c
6a–c
O
CO2Et
O
C
minor
major
O
R1
N
a: R1 = PMP, R2 = PMP (70%)
b: R1 = PMP, R2 = Ph (72%)
c: R1 = Ph, R2 = PMP (70%)
O
R2
H
H
H
5' not formed
H
R2
CO2Et
O
Scheme 1 Reagents and conditions: (a) 2,2-dimethoxy propane,
benzene, PTSA, reflux, 5 h; (b) (i) NaOH, THF–H2O, r.t., 4–6 h;
(ii) (COCl)2, CH2Cl2, reflux, 5 h; (c) R1N=CHR2 (4a–c), Et3N,
CH2Cl2, –40 °C to r.t., 15 h.
R1
N
O
6' not formed
O
Figure 3 Theoretically possible products from diethyl tartrate
derived ketene
methane24,27 (Scheme 2). One of the diols 8b derived from
minor diastereomer 6b offered crystalline product. It
helped to establish the absolute configuration of the b-lac-
tam ring carbons via X-ray analysis.25 Minor diastereomer
8b (Figure 4) was found to have 3R,4R absolute con-
figuration.
R2
O
COOEt
OH
O
O
H
b
a
R1
N
H
5a–c
N
OH
R1
H
R2
7a–c
9a–c
R2
N
H
COOEt
OH
O
R2
H
b
a
R1
6a–c
N
OH
O
R1
H
O
8a–c
10a–c
Figure 2 ORTEP diagram of 5a
Scheme 2 Reagents and conditions: (a) FeCl3, CH2Cl2, r.t., 2 h;
(b) NaIO4, acetone–water, r.t., 6–8 h.
from four directions, theoretically four diastereomers are
possible. We envisaged that the torquoelectronic effect26
of the oxygen substituent on the ketene would prohibit
attack from its side, thereby completely eliminating the
possibility of formation of products 5¢ and 6¢. Reaction in-
deed followed the expected course and the only products
obtained were 5a–c and 6a–c, which arise from the attack
of imine taking place from the opposite side of the oxygen
substituent. The ethoxy carbonyl substituent due to its
lesser bulk and distance from the reaction center exerted
only little steric influence resulting into low diastereose-
lectivity. However, both the diastereomers could be easily
separated by careful flash column chromatography.
Figure 4 ORTEP diagram of 8b
Deprotection of acetonide to furnish diols 7a–c and 8a–c
proceeded cleanly using anhydrous FeCl3 in dichloro-
Synlett 2007, No. 14, 2242–2246 © Thieme Stuttgart · New York

2244
P. M. Chincholkar et al.
LETTER
The oxidative cleavage of these diols 7a–c and 8a–c by
sodium periodate in acetone–water mixture24 provided the
corresponding azetidine-2,3-diones 9a–c and 10a–c in
excellent yields (Table 1). Major diastereomers of spiro-
b-lactams yielded (4S)-azetidine-2,3-diones, while minor
diastereomers furnished (4R)-azetidine-2,3-diones.
References and Notes
(1) For reviews on b-lactam antibiotics, see: (a) Durkheimer,
W.; Blumbatch, J.; Lattrell, R.; Scheunemann, K. H. Angew.
Chem., Int. Ed. Engl. 1985, 24, 180. (b) Chemistry and
Biology of b-Lactam Antibiotics, Vol. 1; Morin, R. B.;
Gorman, M., Eds.; Academic Press: New York, 1982.
(c) Chemistry and Biology of b-Lactam Antibiotics, Vol. 2;
Morin, R. B.; Gorman, M., Eds.; Academic Press: New
York, 1982. (d) Chemistry and Biology of b-Lactam
Antibiotics, Vol. 3; Morin, R. B.; Gorman, M., Eds.;
Academic Press: New York, 1982. (e) Coulton, S.; Hunt, E.
In Recent Progress in the Chemical Synthesis of Antibiotics
and Related Microbial Products, Vol. 2; Lukacs, G., Ed.;
Springer-Verlag: Berlin, 1993, 621. (f) Southgate, R.
Contemp. Org. Synth. 1994, 1, 417. (g) The Chemistry of b-
Lactams; Page, M. I., Ed.; Chapman and Hall: London,
1992.
(2) Rothstein, J. D.; Patel, S.; Regan, M. R.; Haenggelli, C.;
Huang, Y. H.; Bergles, D. E.; Jin, L.; Hoberg, M. D.;
Vidensky, S.; Chung, D. S.; Toan, S. V.; Bruijn, L. I.; Su, Z.-
Z.; Gupta, P.; Fisher, P. B. Nature (London) 2005, 433, 73.
(3) (a) Burnett, D. A.; Caplen, M. A.; Davis, H. R. Jr.; Burrie, R.
E.; Clader, J. W. J. Med. Chem. 1994, 37, 1733. (b) Dugar,
S.; Yumibe, N.; Clader, J. W.; Vizziano, M.; Huie, K.; van
Heek, M.; Compton, D. S.; Davis, H. R. Jr. Bioorg. Med.
Chem. Lett. 1996, 6, 1271. (c) Wu, G. G. Process Res. Det.
2004, 4, 298.
(4) Han, W. T.; Trehan, A. K.; Wright, J. J. K.; Federici, M. E.;
Seiler, S. M.; Meanwell, N. A. Bioorg. Med. Chem. 1995, 3,
1123.
(5) Borthwick, A. D.; Weingarten, G.; Haley, T. M.;
Tomaszewski, M.; Wang, W.; Hu, Z.; Bedard, J.; Jin, H.;
Yuen, L.; Mansour, T. S. Bioorg. Med. Chem. Lett. 1998, 8,
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(6) Cainelli, G.; Galletti, P.; Garbisa, S.; Giacomini, D.; Sartor,
L.; Quintavalla, A. Bioorg. Med. Chem. 2003, 11, 5391.
(7) (a) Doherty, J. B.; Ashe, B. M.; Agrenbright, L. W.; Baker,
P. L.; Bonney, R. J.; Chandler, G. O.; Dahlgren, M. E.; Dorn,
C. P. Jr.; Finke, P. E.; Firestone, R. A.; Fletcher, D.;
Hagemann, W. K.; Munford, R.; O’Grady, L.; Maycock, A.
L.; Pisano, J. M.; Shah, S. K.; Thompson, K. R.;
Zimmerman, M. Nature (London) 1986, 322, 192.
(b) Cvetovich, R. J.; Chartran, M.; Hartner, F. W.; Roberge,
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6575.
(8) (a) Zhou, N. E.; Guo, D.; Thomas, G.; Reddy, A. V. N.;
Kaleta, J.; Purisima, E.; Menard, R.; Micetich, R. G.; Singh,
R. Bioorg. Med. Chem. Lett. 2003, 13, 139. (b) Setti, E. L.;
Davis, D.; Chung, T.; McCarter, J. Bioorg. Med. Chem. Lett.
2001, 11, 2051.
Table 1 Synthesis of Azetidine-2,3-diones 9a–c and 10a–c
Entry
b-Lactam Diones
Yield (%)a [a]D26 (CHCl3)
1
2
3
4
5
6
5a
5b
5c
6a
6b
6c
9a
74
78
81
77
74
75
+53.3 (c = 0.9)
+123.0 (c = 2.0)
+80.0 (c = 0.8)
–54.6 (c = 1.5)
–123.6 (c = 1.1)
–79.2 (c = 5.3)
9b
9c
10a
10b
10c
a Isolated overall yields from spiro-b-lactam 5a–c and 6a–c.
Stereoselective reduction of the keto group of racemic
azetidin-2,3-diones to the corresponding 3-hydroxy azeti-
din-2-ones with sodium borohydride is known.28 To con-
firm the absolute configuration of azetidin-2,3-diones we
carried out reduction of one of the diones (9b) to a known
3-hydroxy b-lactam. The spectral data and the specific
rotation29 {(3R,4S)-3-hydroxy-1-(4-methoxyphenyl)-4-
phenyl azetidin-2-one; observed [a]D26 +177.7 (c = 0.18,
CHCl3); Lit.29 [a]D +176.0 (c = 1.00, CHCl3)} were in
good agreement with those of the reported compound. 3-
Hydroxy-4-aryl b-lactams are also important synthetic
targets as they have been shown to be synthons for the
phenyl isoserine side chain of taxol30,31 and all the four
isomers of cytoxazone.32
In conclusion, we have developed a short synthesis of
azetidine-2,3-diones from L-(+)-diethyl tartrate. This
work represents the first report describing a convenient
access to enantiopure azetidine-2,3-diones with aromatic
substituents at the N-1 and C-4 positions of the b-lactam.
The methodology consists of fewer steps, is operationally
simple and can be adopted for large-scale preparation.
Enantiopure 3-hydroxy b-lactams can also be accessed
easily from azetidine-2,3-diones in good yields.
(9) (a) Smith, D. M.; Kazi, A.; Smith, L.; Long, T. E.; Heldreth,
B.; Turos, E.; Dou, Q. P. Mol. Pharmacol. 2002, 61, 1348.
(b) Kazi, A.; Hill, R.; Long, T. E.; Kuhn, D. J.; Turos, E.;
Dou, Q. P. Biochem. Pharmacol. 2004, 67, 365.
Acknowledgment
(10) (a) Alonso, E.; Lopez-Ortiz, F.; del Pozo, C.; Peratta, E.;
Macias, A.; Gonzalez, J. J. Org. Chem. 2001, 66, 6333.
(b) Bittermann, H.; Gmeiner, P. J. Org. Chem. 2006, 71, 97.
(11) Alonso, E.; del Pozo, C.; Gonzalez, J. Synlett 2002, 69.
(12) (a) Broccolo, F.; Carnally, G.; Caltabiano, G.; Cocuzza, C.
E. A.; Fortuna, C. G.; Galletti, P.; Giacomini, D.;
Musumarra, G.; Musumeci, R.; Quitavalla, A. J. Med. Chem.
2006, 49, 2804. (b) Alcaide, B.; Almendros, P. Curr. Med.
Chem. 2004, 11, 1921. (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) Singh,
G. S. Tetrahedron 2003, 59, 7631. (e) Alcaide, B.;
The authors thank DST, New Delhi, for financial support and
P.M.C. thanks UGC, New Delhi, for a research fellowship. We also
thank Mr. R. G. Gonnade for his help during X-ray diffraction
studies.
Synlett 2007, No. 14, 2242–2246 © Thieme Stuttgart · New York

LETTER
An Efficient Synthesis of Azetidine-2,3-diones from L-(+)-Diethyl Tartrate
2245
Almendros, P. Synlett 2002, 381. (f) Palomo, C.; Aizpurua,
3.74 (s, 3 H, Me), 3.81 (s, 3 H, Me), 4.16–4.29 (m, 2 H,
OCH2), 5.02 (s, 1 H, C8-H), 5.19 (s, 1 H, C3-H), 6.79 (d, J =
8.9 Hz, 2 H, ArH), 6.91 (d, J = 8.9 Hz, 2 H, ArH), 7.25–7.31
(m, 4 H, ArH). 13C NMR (50 MHz, CDCl3): d = 13.7, 25.6,
26.5, 55.1, 55.2, 61.8, 68.0, 78.1, 92.5, 113.6, 113.9, 114.1,
118.7, 124.9, 129.2, 130.3, 156.2, 159.8, 163.3, 167.9. MS:
m/z = 442 [M + 1]. Anal. Calcd for C24H27NO7: C, 65.29; H,
6.16; N, 3.17. Found: C, 65.18; H, 6.29; N, 3.03.
J. M.; Ganboa, I.; Oiarbid, M. Synlett 2001, 1813.
(g) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbid, M. In
Enantioselective Synthesis of b-Amino Acids; Juaristi, E.,
Ed.; Wiley-VCH: New York, 1997, 279.
(13) Palomo, C.; Aizpurua, J. M.; Urchegui, R.; Garcia, J. M.
J. Chem. Soc., Chem. Commun. 1995, 2327.
(14) (a) Jayaraman, M.; Manhas, M. S.; Bose, A. K. Tetrahedron
Lett. 1997, 38, 709. (b) Kant, J.; Schwartz, W. S.; Fairchild,
C.; Gao, Q.; Huang, S.; Long, B. H.; Kadow, J. F.; Langley,
D. R.; Farina, V.; Vyas, D. Tetrahedron Lett. 1996, 37,
6495. (c) Palomo, C.; Aizpurua, J. M.; Lopez, M. C.;
Aurrekoetxea, N.; Oiarbide, M. Tetrahedron Lett. 1990, 31,
6425. (d) Palomo, C.; Aizpurua, J. M.; Cossio, F. P.; Garcia,
J. M.; Lopez, M. C.; Oiarbide, M. J. Org. Chem. 1990, 55,
2070. (e) Palomo, C.; Aizpurua, J. M.; Lopez, M. C.;
Aurrekoetxea, N.; Oiarbide, M. Tetrahedron Lett. 1990, 31,
2205. (f) Tiwari, D. K.; Gumaste, V. K.; Deshmukh, A. R.
A. S. Synthesis 2006, 115.
(15) (a) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Odriozola, B.;
Maneiro, E.; Miranda, J. I.; Urchegui, R. Chem. Commun.
1996, 161. (b) Palomo, C.; Aizpurua, J. M.; Ganboa, I.;
Carreaux, F.; Cuevas, C.; Maneiro, E.; Ontoria, J. M. J. Org.
Chem. 1994, 59, 3123.
(3R,4R,8R)-1,2-Bis(4-methoxyphenyl)-6,6-dimethyl-3-
oxo-5,7–dioxa-2-azaspiro[3.4]octane-8-carboxylic Acid
26
Ethyl Ester (6a): yield: 28%; brown viscous liquid; [a]D
–7.0 (c = 2.8, CHCl3). IR (CHCl3): 1751, 1755 cm–1. 1H
NMR (200 MHz, CDCl3): d = 1.06 (s, 3 H, Me), 1.11 (t,
J = 7.2 Hz, 3 H, OCH2CH3), 1.47 (s, 3 H, Me), 3.75 (s, 3 H,
Me), 3.80 (s, 3 H, Me), 4.18–4.30 (m, 2 H, OCH2CH3), 4.87
(s, 1 H, C3-H), 5.03 (s, 1 H, C8-H), 6.79 (d, J = 9.0 Hz, 2 H,
ArH), 6.87 (d, J = 9.0 Hz, 2 H, ArH), 7.25–7.30 (m, 4 H,
ArH). 13C NMR (50 MHz, CDCl3): d = 13.8, 25.6, 26.1,
55.0, 55.2, 61.7, 65.7, 77.0, 90.9, 113.1, 113.7, 114.2, 118.7,
124.5, 129.1, 130.3, 156.3, 159.7, 163.4, 167.6. MS: m/z =
442 [M + 1]. Anal. Calcd for C24H27NO7: C, 65.29; H, 6.16;
N, 3.17. Found: C, 65.42; H, 6.10; N, 3.25.
Typical Procedure for Diol 7a: To a solution of spiro-b-
lactam 5a (0.200 g, 0.453 mmol) in dichloromethane (10
mL) was added anhyd FeCl3 (0.147 g, 0.907 mmol) at r.t. and
stirred for 2 h. After completion of the reaction (TLC) the
reaction mixture was passed through a celite bed. The filtrate
was concentrated in vacuo to get the crude diol 7a. The crude
product was purified by column chromatography [PE–
EtOAc (3:2)] to obtain pure diol 7a (0.162 g, 89%).
(16) Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem.
Commun. 2000, 757.
(17) Cossio, F. P.; Lopez, C.; Oiarbide, M.; Palomo, C.;
Apariocio, D.; Rubiales, G. Tetrahedron Lett. 1988, 29,
3133.
(18) Cossio, F. P.; Ganboa, I.; Garcia, J. M.; Lecea, B.; Palomo,
C. Tetrahedron Lett. 1987, 28, 1945.
(3S,4S)-Hydroxy-[3-hydroxy-1,2-bis(4-methoxyphenyl)-
4-oxoazetidin-3-yl]acetic Acid Ethyl Ester (7a): yield:
89%; thick brown oil; [a]D26 +20 (c = 1.1, CHCl3). IR
(CHCl3): 1731, 1735, 3377 cm–1. 1H NMR (200 MHz,
CDCl3): d = 1.29 (t, J = 7.1 Hz, 3 H, OCH2CH3), 2.05 (s, 2
H, OH), 3.75 (s, 3 H, OMe), 3.80 (s, 3 H, OMe), 4.32 (quart,
J = 7.1 Hz, 2 H, OCH2CH3), 5.27 (s, 1 H, CHCOOEt), 5.30
(s, 1 H, C4-H), 6.79 (d, J = 9.0 Hz, 2 H, ArH), 6.91 (d, J =
8.9 Hz, 2 H, ArH), 7.21–7.30 (m, 4 H, ArH). 13C NMR (50
MHz, CDCl3): d = 13.9, 55.1, 55.3, 62.3, 63.3, 71.0, 86.3,
114.1, 119.0, 124.5, 129.0, 130.0, 156.3, 159.8, 164.2,
171.5. MS: m/z = 402 [M + 1]. Anal. Calcd for C21H23NO7:
C, 62.83; H, 5.78; N, 3.49. Found: C, 62.72; H, 5.94; N, 3.60.
(3R,4R)-Hydroxy-[3-hydroxy-1,2-bis(4-methoxyphenyl)-
4-oxo-azetidin-3-yl]acetic Acid Ethyl Ester (8a): yield:
88%; thick brown oil; [a]D26 –25.6 (c = 2.5, CHCl3). IR
(CHCl3): 1731, 1737, 3371 cm–1. 1H NMR (200 MHz,
CDCl3): d = 1.26 (t, J = 7.2 Hz, 3 H, OCH2CH3), 2.04 (s, 2
H, OH), 3.74 (s, 3 H, OMe), 3.79 (s, 3 H, OMe), 4.30 (quart,
J = 7.2 Hz, 2 H, OCH2CH3), 4.63 (s, 1 H, C4-H), 5.30 (s, 1
H, CHCOOEt), 6.78 (d, J = 9.1 Hz, 2 H, ArH), 6.91 (d, J =
8.9 Hz, 2 H, ArH), 7.23–7.30 (m, 4 H, ArH). 13C NMR (50
MHz, CDCl3): d = 13.5, 55.2, 55.3, 61.9, 63.2, 71.1, 86.8,
114.1, 119.2, 124.5, 129.1, 130.0, 156.9, 159.7, 164.3,
171.5. MS: m/z = 402 [M + 1]. Anal. Calcd for C21H23NO7:
C, 62.83; H, 5.78; N, 3.49. Found: C, 62.75; H, 5.69; N, 3.32.
Typical Procedure for Dione 9a: To a solution of diol 7a
(0.105 g, 0.261 mmol) in acetone–water (2:1, 6 mL) was
added powdered NaIO4 and the solution was stirred for
6–8 h. After completion of the reaction (TLC), the reaction
mixture was filtered through a Büchner funnel and the
residue was washed with acetone (5 mL). The combined
filtrates were evaporated in vacuo to remove acetone. The
residue was extracted with dichloromethane (3 × 10 mL).
The combined organic extracts were washed with brine (10
mL), dried over Na2SO4 and concentrated under reduced
pressure to get the crude dione 9a as a yellow solid. The
(19) (a) Manhas, M. S.; Bari, S. S.; Bhawal, B. M.; Bose, A. K.
Tetrahedron Lett. 1984, 25, 4733. (b) Van der Veen, J. M.;
Bari, S. S.; Krishnan, L.; Manhas, M. S.; Bose, A. K.
J. Org. Chem. 1989, 54, 5758.
(20) (a) Tufariello, J. J.; Pinto, D. J. P.; Milowsky, A. S.;
Reinhardt, D. V. Tetrahedron Lett. 1987, 28, 5481.
(b) Lysek, R.; Lipkowska, Z. U.; Chmielewski, M.
Tetrahedron 2001, 57, 1301. (c) Danh, T. T.; Borsuk, K.;
Solecka, J.; Chmielewski, M. Tetrahedron 2006, 62, 10928.
(21) Kai, H.; Orita, A.; Murai, S. Synth. Commun. 1998, 28, 1989.
(22) (a) Burnett, D. A.; Caplen, M. A.; Davis, H. R. Jr.; Burrier,
R. E.; Clader, J. W. J. Med. Chem. 1994, 37, 1733.
(b) Burnett, D. A. Tetrahedron Lett. 1994, 37, 7339.
(23) Carmack, M.; Kelly, C. J. J. Org. Chem. 1968, 33, 2171.
(24) Typical Procedure for Spiro-b-lactams 5a and 6a: A
solution of acid chloride 3 (0.371 g, 1.84 mmol) in anhyd
dichloromethane (10 mL) was added dropwise over a period
of 20–30 min to a solution of imine 4a (0.296 g, 1.23 mmol)
and triethyl amine (0.77 mL, 5.53 mmol) in anhyd
dichloromethane (20 mL) at –40 °C. After the addition was
complete the solution was allowed to attain r.t. and stirred
for 15 h (TLC). The reaction mixture was then diluted with
dichloromethane and washed with H2O (2 × 10 mL) and sat.
brine solution (10 mL). The combined organic layer was
dried over anhyd Na2SO4, filtered and concentrated under
reduced pressure to get the crude diastereomeric mixture of
5a and 6a (0.480 g, 70%). 1H NMR of the crude product
showed a 60:40 mixture of diastereomers which were
separated by careful flash column chromatography [PE–
EtOAc (8:2)].
(3S,4S,8R)-1,2-Bis(4-methoxyphenyl)-6,6-dimethyl-3-
oxo-5,7–dioxa-2-azaspiro[3.4]octane-8-carboxylic Acid
Ethyl Ester (5a): yield: 42%; colorless crystals; mp 163–
164 °C; [a]D26 +1.4 (c = 2.7, CHCl3). IR (CHCl3): 1751,
1755 cm–1. 1H NMR (200 MHz, CDCl3): d = 1.04 (s, 3 H,
Me), 1.12 (t, J = 7.2 Hz, 3 H, OCH2CH3), 1.60 (s, 3 H, Me),
Synlett 2007, No. 14, 2242–2246 © Thieme Stuttgart · New York

2246
P. M. Chincholkar et al.
LETTER
reflections measured, 4083 unique [I > 2s(I)], R value =
crude product was purified by column chromatography
[PE–EtOAc (8:2)] to get pure dione 9a as a yellow solid
(0.065 g, 84%).
0.0482, wR2 = 0.1268. X-ray analysis revealed the
stereochemistry at C(3) and C(4) positions. The
supplementary crystallographic data can be obtained free of
charge from the Cambridge Crystallographic Data Centre
via www.ccdc.cam.uk/data_request/cif. Please quote the
reference number CCDC 647625.
(4S)-1,4-Bis(4-methoxyphenyl)azetidine-2,3-dione (9a):
yield: 84%; yellow solid; mp 144 °C; [a]D26 +53.3 (c = 0.9,
CHCl3). IR (CHCl3): 1755, 1809, 1832 cm–1. 1H NMR (200
MHz, CDCl3): d = 3.79 (s, 3 H, OMe), 3.80 (s, 3 H, OMe),
5.51 (s, 1 H, C4-H), 6.85–6.94 (m, 4 H, ArH), 7.24 (d, J =
9.3 Hz, 2 H, ArH), 7.46 (d, J = 9.1 Hz, 2 H, ArH). 13C NMR
(50 MHz, CDCl3): d = 55.2, 55.4, 74.4, 114.6, 114.8, 119.6,
123.5, 127.7, 129.8, 157.8, 160.1, 160.8, 191.1. MS: m/z =
298 [M + 1]. Anal. Calcd for C17H15NO4: C, 68.68; H, 5.09;
N, 4.71. Found: C, 68.85; H, 5.19; N, 4.62.
(4R)-1,4-Bis(4-methoxyphenyl)azetidine-2,3-dione (10a):
yield: 85%; [a]D26 –54.6 (c = 1.5, CHCl3). The spectral data
of 10a was identical to that of 9a. Anal. Calcd for
C17H15NO4: C, 68.68; H, 5.09; N, 4.71. Found: C, 68.50; H,
5.22; N, 4.67.
Crystal Data for 8b (C20H21NO6): M = 371.38; crystal
dimensions: 0.51 × 0.11 × 0.03 mm, hemisphere data
acquisition. Total scans = 3, total frames = 1271, exposure/
frame = 15.0 s/frame, range = 2.07°–24.99°, completeness to
of 24.99º: 99.4%. Crystals belonged to monoclinic, space
group P21, a = 11.324(1) Å, b = 5.3940(7) Å, c = 15.822(2)
Å, b = 98.893(3)°, V = 954.8(2) Å3, Z = 2, Dc = 1.292 mg/m3,
m (MoKa) = 0.096 mm–1, T = 293(2) K, 4764 reflections
measured, 2759 unique [I >2s(I)], R value = 0.0696, wR2 =
0.1552. X-ray analysis revealed the stereochemistry at C(3)
and C(4) positions. The end atom C(19) had positional
disorder. The supplementary crystallographic data can be
obtained free of charge from the Cambridge
(25) X-ray Data for 5a and 8b: Single crystals of the 5a and 8b
were grown by slow evaporation of the solution mixture in
EtOAc and PE. The X-ray data of 5a–8b were collected on
a SMART APEX CCD single crystal X-ray diffractometer
with omega and phi scan mode and different number of
scans and exposure times for different crystals using
l(MoKa) = 0.71073 Å radiation at T = 293 (2) K with
oscillation/frame = –0.3°, maximum detector swing angle =
–30.0°, beam center = (260.2, 252.5), in plane spot width =
1.24. All the data were corrected for Lorentzian, polarization
and absorption effects using SAINT and SADABS
programs. The crystal structures were solved by direct
method using SHELXS-97 and the refinement was
performed by full matrix least squares of F2 using SHELXL-
97.33
Crystallographic Data Centre via www.ccdc.cam.uk/
data_request/cif. Please quote the reference number CCDC
647624.
(26) Alonso, E.; del Pozo, C.; Gonzalez, J. J. Chem. Soc., Perkin
Trans. 1 2002, 571.
(27) Sen, S. E.; Roach, S. L.; Boggs, J. K.; Ewing, G. J.; Magrath,
J. J. Org. Chem. 1997, 62, 6684.
(28) Palomo, C.; Arrieta, A.; Cossio, F. P.; Aizpurua, J. M.;
Mielgo, A.; Aurrekoetxea, N. Tetrahedron Lett. 1990, 31,
6429.
(29) Srirajan, V.; Deshmukh, A. R. A. S.; Bhawal, B. M.
Tetrahedron 1996, 52, 5585.
(30) Denis, J.-N.; Greene, A. E.; Serra, A. A.; Luche, M. J. J. Org.
Chem. 1986, 51, 46.
(31) Denis, J.-N.; Greene, A. E.; Gueritte-Voegelein, F.;
Mangatal, L.; Potier, P. J. Am. Chem. Soc. 1988, 110, 5917.
(32) Mishra, R. K.; Coates, C. M.; Revell, K. D.; Turos, E. Org.
Lett. 2007, 9, 575.
(33) Sheldrick, G. M. SHELX-97: Program for Crystal Structure
Solution and Refinement; University of Göttingen:
Germany, 1997.
Crystal Data for 5a (C24H27NO7): M = 441.47; crystal
dimensions: 0.52 × 0.47 × 0.33 mm, multirun data
acquisition. Total scans = 3, total frames = 1818, exposure/
frame = 10.0 s/frame, range = 1.98°–27.00°, completeness to
of 27.0°: 100.0%. Crystals belonged to monoclinic, space
group P21/c, a = 10.8952(5) Å, b = 23.954(1) Å, c =
9.4343(5) Å, b = 109.280(3)°, V = 2324.1(2) Å3, Z = 4, Dc =
1.262 mg/m3, m (MoKa) = 0.093 mm–1, T = 293(2) K, 16695
Synlett 2007, No. 14, 2242–2246 © Thieme Stuttgart · New York

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