Synthesis of 4-dendronized β-lactams

Article abstract of DOI:10.1055/s-2003-40990

The first synthesis of 4-dendronized β-lactams using the standard Staudinger ketene-imine cyclization is described. Both ±-conjugated and Fre?chet's aromatic polyether dendrons having imine focal points were used as starting materials. Exclusive cisstereochemistry was observed for all the β-lactams prepared.

Full text of DOI:10.1055/s-2003-40990

LETTER
1587
Synthesis of 4-Dendronized b-Lactams
S
ynthesis of 4-D
n
endronize
d
r
b
-Lactam
i
s
que Díez-Barra, Joaquín C. García-Martínez, Julián Rodríguez-López*
Área de Química Orgánica, Facultad de Química, Universidad de Castilla-La Mancha, 13071-Ciudad Real, Spain
Fax +34(926)295318; E-mail: julian.rodriguez@uclm.es
Received 9 May 2003
Classical condensation of the dendritic aldehydes with a
slight excess of p-anisidine in CH2Cl2 in the presence of
molecular sieves (4 Å) afforded smoothly the expected
dendritic imines (Table 1).11 Purification of these com-
pounds was performed easily and efficiently by washing
the crude product with ethanol in order to solubilize the
excess of amine, and filtering off the pure desired imine.
Abstract: The first synthesis of 4-dendronized b-lactams using the
standard Staudinger ketene–imine cyclization is described. Both
p-conjugated and Fréchet’s aromatic polyether dendrons having
imine focal points were used as starting materials. Exclusive cis-
stereochemistry was observed for all the b-lactams prepared.
Key words: dendrimers, b-lactams, imines, ketenes, Staudinger re-
action
The synthesis of the 4-dendronized b-lactams was
achieved following a standard methodology.8b Thus, treat-
ment of imines 1a,b with isobutyryl chloride and phe-
noxyacetyl chloride, respectively, in dichloromethane at
room temperature and in the presence of triethylamine
gave b-lactams 2a,b. In addition, enantiomerically pure 2-
azetidinones 2c–f12 were obtained from (+)-(S)-(4-phe-
nyl-2-oxo-1,3-oxazolidin-3-yl)acetic acid and the corre-
sponding imines 1b–e in the presence of triethylamine and
dichlorophenylphosphate as condensating agent in the
same solvent (Table 2).
Dendrimers are a unique class of compounds, which have
been largely studied during the last two decades. Synthet-
ic methodologies for dendrimers are well known1 and the
wide scope of their applications is continuously growing.2
One of the more promising field for dendrimers is their
use for biomedical applications. Their ability to be used
for diagnostics and therapy (including magnetic reso-
nance imaging, drug-delivery, DNA biosensors, boron
neutron-capture therapy, etc.), and as new polymeric bio-
materials for tissue engineering, has been recently re-
viewed.3
It is noteworthy that exclusive cis-stereochemistry was
observed for all b-lactams 2 prepared as determined by
1
On the other hand, the synthesis of new 2-azetidinone de-
rivatives is a permanent goal4 because of the wide pres-
ence of this ring in antibiotics, the increased bacterial-
resistance to natural b-lactam antibiotics and, more re-
cently, the development of nonantibiotic uses.5
high field H NMR analysis of the crude reaction mix-
tures. It was established by the value of coupling constants
of the H3-H4 protons (J = ca. 5 Hz). No traces of the
trans-isomers were detected in any case. As exemplified
by compound 2f, the stereochemical outcome of the reac-
tion did not suffer any variation even with substituents as
large as a third generation Fréchet dendron.
Thus, dendronized b-lactams would incorporate in a
unique structure two of the most interesting classes of
compounds. However, surprisingly, b-lactams having
dendritic substituents attached to the four-membered ring
have not been reported yet. To the best of our knowledge,
there are only two papers where dendrimers and b-lactams
are related. One of them describes the use of a carbosilane
dendrimer for the synthesis of a library of b-lactams;6 the
other one concerns the use of PAMAM for preparing
densely penicilloylated dendrimers.7
The clean and high efficiency of the reactions employed
facilitated product isolation and purification. The struc-
ture and purity of all the new compounds described herein
has been confirmed using MS, NMR, IR, and elemental
analysis. HRMS analyses of 2a,b,e gave the expected mo-
lecular ions. The MALDI-TOF spectra of 2c,d,f showed
peaks matching the calculated values for the expected mo-
lecular weights (Table 3).
Herein we describe the first synthesis of a set of b-lactams
that incorporates different dendritic wedges (up to third
generation) at the 4-position of the 2-azetidinone ring.
The synthesis has been envisaged following the classical
Staudinger approach based on the reaction of imines and
ketenes.8
In conclusion, we have demonstrated that the standard
Staudinger ketene–imine cyclization can be used to effi-
ciently prepare in a complete stereoselective manner the
hitherto unknown cis-3-substituted-4-dendronized b-lac-
tams 2. This strategy is extremely general, permitting not
only the use of different ketene derivatives as starting ma-
terials but also the introduction at the 4-position of the 2-
azetidinone ring of both p-conjugated and Fréchet’s type
dendritic branches.
The required dendritic imines were prepared from both p-
conjugated dendrons, previously reported by us,9 and
Fréchet’s type dendrons10 having formyl focal points.
Further transformations and applications of the prepared
dendronized b-lactams are currently investigated in our
laboratories.
Synlett 2003, No. 11, Print: 02 09 2003. Web: 05 08 2003.
Art Id.1437-2096,E;2003,0,11,1587,1590,ftx,en;G10403ST.pdf.
DOI: 10.1055/s-2003-40990
© Georg Thieme Verlag Stuttgart · New York

1588
E. Díez-Barra et al.
LETTER
Table 1 Preparation of Dendritic Imines
O
CH2Cl2
N
OCH3
H2N
OCH3
Dend
+
Dend
molecular sieves
1
Entry
Dend
Imine
Yield (%)a
1
1a
81
NC
CN
2
1b
87
3
1c
98
O
O
O
4
1d
92
O
O
O
O
O
O
O
O
O
O
5
1e
85
O
O
O
O
O
O
O
a Not optimized isolated yields.
Synlett 2003, No. 11, 1587–1590 © Thieme Stuttgart · New York

LETTER
Synthesis of 4-Dendronized b-Lactams
1589
Table 2 Preparation of 4-Dendronized b-Lactams
References
(1) (a) Newkome, G. R.; Moorefield, C. N.; Vögtle, F.
Dendrimers and Dendrons; Wiley-VCH: Weinheim, 2001.
(b) Dendrimers and Other Dendritic Polymers; Fréchet, J.
M. J.; Tomalia, D. A., Eds.; Wiley: Chichester, 2001.
(c) Topics Curr. Chem.; Vögtle, F., Ed.; Springer:
Heidelberg, 1998, 197. (d) Bosman, A. W.; Janssen, H. M.;
Meijer, E. W. Chem. Rev. 1999, 99, 1665. (e) Majoral, J. P.;
Caminade, A. M. Chem. Rev. 1999, 99, 845. (f) Zeng, F.;
Zimmerman, S. C. Chem. Rev. 1997, 97, 1681. (g) Smith,
D. K.; Diederich, F. Chem.–Eur. J. 1998, 4, 1353.
(2) (a) Fischer, M.; Vögtle, F. Angew. Chem. Int. Ed. 1999, 38,
884. (b) Issberner, J.; Moors, R.; Vögtle, F. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 2413.
20
Entry
R
R¢
Starting b-Lactam Yield [a]D
Imine
(%)a
(CH3Cl)c
(3) (a) Stiriba, S.-E.; Frey, H.; Haag, R. Angew. Chem. Int. Ed.
2002, 41, 1329. (b) Grinstaff, M. W. Chem.–Eur. J. 2002, 8,
2839.
(4) For a recent review see: Gómez-Gallego, M.; Mancheño, M.
J.; Sierra, M. A. Tetrahedron 2000, 56, 5743.
(5) (a) Wilmouth, R. C.; Kassamally, S.; Westwood, N. J.;
Sheppard, R. J.; Claridge, T. D. W.; Aplin, R. T.; Wright, P.
A.; Pritchard, G. J.; Schofield, C. J. Biochemistry 1999, 38,
7989. (b) Taylor, P.; Anderson, V.; Dowden, J.; Flitsch, S.
L.; Turner, N. J.; Loughran, K.; Walkinshaw, M. D. J. Biol.
Chem. 1999, 274, 24901.
(6) Hovestad, N. J.; Ford, A.; Jastrzebski, J. T. B. H.; van Koten,
G. J. Org. Chem. 2000, 65, 6338.
(7) Sánchez-Sancho, F.; Pérez-Inestrosa, E.; Suau, R.; Mayorga,
C.; Torres, M. J.; Blanca, M. Bioconjugate Chem. 2002, 13,
647.
(8) (a) Staudinger, M. Liebigs Ann. Chem. 1907, 356, 51.
(b) For a recent use of this approach see: Alcaide, B.;
Rodríguez-Campos, I. M.; Rodríguez-López, J.; Rodríguez-
Vicente, A. J. Org. Chem. 1999, 64, 5377.
1
2
3
CH3
CH3
H
1a
2a
2b
2c
92
–
–
PhO
1b
80
S-Oxb
H
1c
75
+32.9º
(c 0.07)
4
5
6
S-Oxb
S-Oxb
S-Oxb
H
H
H
1b
1d
1e
2d
2e
2f
90
72
54
–1.7º
(c 1.18)
+49.0
(c 0.05)
+29.0
(c 0.03)
a Not optimized isolated yields.
b S-Ox = (S)-4-phenyl-2-oxo-1,3-oxazolidin-3-yl.
c Concentration in g/100 mL
(9) (a) Díez-Barra, E.; García-Martínez, J. C.; Merino, S.; del
Rey, R.; Rodríguez-López, J.; Sánchez-Verdú, P.; Tejeda, T.
J. Org. Chem. 2001, 66, 5664. (b) Díez-Barra, E.; García-
Martínez, J. C.; Rodríguez-López, J. J. Org. Chem. 2003, 68,
832.
Acknowledgment
Financial support from the Spanish DGI (BQU2002-01327), and
the Junta de Comunidades de Castilla-La Mancha (GC-02-013) is
gratefully acknowledged.
Table 3 Mass Spectrometry of Compounds 1 and 2
Entry
Compound
Molecular Formula
C32H23N3O
Methoda
Found
MW Calcd
1
2
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
2f
EI+, HRMS
FAB+, HRMS
FAB+, HRMS
EI+, HRMS
MALDI
465.2 [M+], 465.1834
1556.8 [M+], 1556.0797
1520.7 [M+], 1520.2836
847.6 [M+], 847.3509
1719.8 [M + Na]+
535.65 [M+], 535.2262
1691.6 [M+], 1690.1136
1724.2 [M+]
465.55, 465.1841
1557.33, 1556.0810
1521.47, 1520.2899
848.01, 847.3498
1697.00
C
110H141NO5
102H169NO7
3
C
4
C56H49NO7
112H97NO15
C36H29N3O2
5
C
6
EI+, HRMS
FAB+, HRMS
MALDI
535.65, 535.2260
1691.47, 1690.1178
1724.66
7
C118H147NO7
C113H178N2O10
C121H150N2O8
8
9
MALDI
1783.1 [M + Na]+
1051.2 [M+], 1050.4055
1922.7 [M + Na]+
1760.53
10
11
C67H58N2O10
123H106N2O18
FAB+, HRMS
MALDI
1051.20, 1050.4091
1900.20
C
a FAB+: matrix of m-nitrobenzyl alcohol; MALDI-TOF: matrix of dithranol in the presence of NaI. Spectrum for 2c could be recorded without
Na+ ions.
Synlett 2003, No. 11, 1587–1590 © Thieme Stuttgart · New York

1590
E. Díez-Barra et al.
LETTER
(12) Representative Experimental Procedure for the
(10) Pollak, K. W.; Sanford, E. M.; Fréchet, J. M. J. J. Mater.
Chem. 1998, 8, 519. Alternatively, we have obtained second
and third generation Fréchet’s dendrons having formyl focal
points by oxidation with MnO2 in CH2Cl2 of the
Preparation of b-Lactam 2f: To a cooled solution (0 °C)
under argon of imine 1e (100 mg, 0.06 mmol) and (+)-(S)-
(4-phenyl-2-oxo-1,3-oxazolidin-3-yl)acetic acid in Et3N
(1 mL) and dry CH2Cl2 (3 mL) was added dropwise
dichlorophenylphosphate (14 mL, 0.09 mmol). The cooling
bath was removed and the mixture was stirred at r.t. for 24 h.
Finally, it was quenched with 1 M HCl, extracted with
CH2Cl2 (×3), and dried (MgSO4). After filtration and
evaporation of the solvent under reduced pressure, the crude
product was purified by column chromatography (silica gel,
CH2Cl2) to give 2f as a white solid (60 mg, 54% yield).
[a]D20 = +29.0 (c 0.03, CHCl3). 1H NMR (500 MHz, CDCl3):
d = 3.67 (s, 3 H, OCH3), 3.88 (dd, 1 H, J = 8.5 Hz, J = 7.5
Hz, CH-O), 4.20 (t, 1 H, J = 9.0 Hz, Ph-CH-N), 4.35 (dd, 1
H, J = 8.5 Hz, J = 7.5 Hz, CH-O), 4.54 (d, 1 H, J = 5.0 Hz,
H4), 4.89–5.02 (m including d, 29 H, J = 5.0 Hz, H3 and 14
× CH2), 6.47 (br s, 2 H, arom.), 6.49 (d, 2 H, J = 2.0 Hz,
arom.), 6.56 (t, 4 H, J = 2.0 Hz, arom.), 6.61 (t, 1 H, J = 2.0
Hz, arom.), 6.64 (d, 4 H, J = 2.0 Hz, arom.), 6.67 (d, 8 H,
J = 2.0 Hz, arom.), 6.70 (A of ABq, 2 H, J = 9.0 Hz, arom.),
7.08–7.11 (m, 2 H, arom.), 7.18 (B of ABq, 2 H, J = 9.0 Hz,
arom.), 7.28–7.42 (m, 43 H, arom.). 13C NMR and DEPT
(125 MHz, CDCl3): d = 160.1 (C), 160.0 (C), 159.9 (C),
156.9 (C), 156.2 (C), 139.2 (C), 139.1 (C), 136.7 (C), 136.5
(C), 135.2 (C), 130.8 (C), 129.3 (CH) 129.2 (CH), 128.6
(CH), 128.0 (CH), 127.6 (CH), 118.4 (CH), 114.1 (CH),
106.4 (CH), 106.2 (CH), 106.1 (CH), 103.1 (CH), 101.5
(CH), 101.4 (CH), 70.2 (CH2), 70.0 (CH2), 69.9 (CH2), 69.8
(CH2), 62.5 (CH), 61.3 (CH), 59.6 (CH), 55.3 (OCH3). IR
(KBr): n = 1754 (C=O), 1596 cm–1. MS (MALDI-TOF):
m/z = 1922.7 (M + Na), 1497.5, 1027.1. Anal. Calcd for
C123H106N2O18: C, 77.75; H, 5.62; N, 1.47. Found: C, 77.42;
H, 5.71; N, 1.43.
corresponding dendrons having hydroxymethyl focal points.
(11) Representative Experimental Procedure for the
Preparation of Imine 1b: A solution of the starting
aldehyde (300 mg, 0.21 mmol) and p-anisidine (51 mg, 0.41
mmol) in dry CH2Cl2 (10 mL) was stirred overnight under
argon at r.t. over molecular sieves (4 Å). Then, the molecular
sieves were removed by filtration and the solvent was
evaporated in vacuo. The residue was washed with EtOH in
order to solubilize the excess of p-anisidine, and the
insoluble imine 1b was obtained by filtration as a yellow
solid (280 mg, 87% yield). Further purification could be
obtained by crystallization from CHCl3/EtOH. 1H NMR
(300 MHz, CDCl3): d = 0.88 (t, 12H, 4 × CH3), 1.20–1.50
(m, 72 H, 36 × CH2), 1.79 (m, 8 H, 4 × CH2), 3.85 (s, 3 H,
OCH3), 3.98 (t, 8 H, J = 6.6 Hz, 4 × CH2), 6.90–7.00 (m
including A of ABq, 14 H, J = 8.7 Hz, 4 × CH= and arom.),
7.14 (B of ABq, 4 H, J = 16.5 Hz, 4 × CH=), 7.29 (B of ABq,
2 H, J = 8.7 Hz, arom.), 7.47 (B of ABq, 8 H, J = 8.7 Hz,
arom.), 7.54 (s, 2 H, arom.), 7.55 (s, 4 H, arom.), 7.83 (t, 1
H, J = 1.5 Hz, arom.), 8.04 (d, 2 H, J = 1.5 Hz, arom.), 8.47
(s, 1 H, CH=N). 13C NMR and DEPT (75 MHz, CDCl3): d =
159.1 (C), 158.6 (C), 156.2 (CH), 144.2 (C), 138.2 (C),
136.9 (C), 136.4 (CH), 131.2 (CH), 129.5 (C), 129.3 (CH),
127.8 (CH), 127.7 (CH), 125.3 (CH), 124.6 (CH), 124.2 (C),
123.3 (C), 122.4 (CH), 114.7 (CH), 114.4 (CH), 90.7 (C),
88.0 (C), 68.1 (OCH2), 55.5 (OCH3), 31.9 (CH2), 29.7
(CH2), 29.6 (CH2), 29.6 (CH2), 29.6 (CH2), 29.4 (CH2), 29.4
(CH2), 29.3 (CH2), 26.0 (CH2), 22.7 (CH2), 14.1 (CH3). IR
(KBr): n = 1618 (C=N), 1585, 1512, 1466, 1256 cm–1. MS
(FAB+): m/z= 1556.8. HRMS: m/z calcd for C110H141NO5:
1556.0810. Found: 1556.0797. Anal. Calcd for
C110H141NO5: C, 84.84; H, 9.13; N, 0.90. Found: C, 84.47; H,
9.29; N, 0.81.
Synlett 2003, No. 11, 1587–1590 © Thieme Stuttgart · New York