A new entry to N-unsubstituted β-lactams through a solid-phase approach

Article abstract of DOI:10.1016/S0040-4039(02)02236-0

A remarkable new entry to N-unsubstituted β-lactams using rink resin as the solid-support has been developed.

Full text of DOI:10.1016/S0040-4039(02)02236-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9445–9447
A new entry to N-unsubstituted b-lactams through a
solid-phase approach
Swapan K. Dasgupta and Bimal K. Banik*
The University of Texas M.D. Anderson Cancer Center, Department of Molecular Pathology, Box 89, 1515 Holcombe Blvd.,
Houston, TX 77030, USA
Accepted 8 October 2002
Abstract—A remarkable new entry to N-unsubstituted b-lactams using rink resin as the solid-support has been developed. © 2002
Elsevier Science Ltd. All rights reserved.
A continuous and intense effort has been directed to
developing methods for synthesizing b-lactams because
of their enormous impact on different diseases.1 N-
Unsubstituted b-lactams plays a central role as key
intermediates in the synthesis of several biologically
active antibiotics.2 The importance of these types of
compounds for the semi-synthesis of the novel anti-
cancer agents Taxol and Taxotere is also well docu-
mented.3 Oxidative cleavage by cerric ammonium
nitrate of an activated aromatic moiety attached to the
nitrogen of the b-lactam ring offers the most direct
synthesis of N-unsubstituted b-lactams.4 This method
has some shortcomings, however, since it is very sensi-
tive to acid-labile compounds and in many cases the
yields are poor. To overcome these problems, a syn-
thetic method that employs neutral conditions using
cobalt carbonyl has been reported.5 Many other less
frequently methods known in the literature are not
popular.6 Although these methods tolerate labile func-
tionalities, their practical application is limited. One
alternative we are exploring is the use of solid phase
support.
reactions that take place in homogeneous conditions to
analogous reactions that take place on solid-support.7
Solid-phase synthesis of 1,2,3-trisubstituted b-lactams
using Sasrin resin has been reported in a pioneering
work.8 N-Unsubstituted b-lactams using TentaGel S
resin under a photochemical method has been investi-
gated.9 Encouraged by these two reports and in contin-
uation of our own efforts to synthesize b-lactams10 of
biological significance, we report here a new method of
synthesizing N-unsubstituted 3,4-disubstituted b-lac-
tams using rink resin as the solid support. Although the
use of rink resin in various chemical transformations
has been reported frequently,11 it has never been used in
b-lactam synthesis.
Although a number of methods for synthesizing b-lac-
tam rings have been developed, the Staudinger reaction
is still the best for this purpose.12 To test the feasibility
of the rink resin approach, we prepared a number of
imines first using rink resin and a variety of aldehydes
using trimethyl orthoformate. Then cycloaddition was
performed on these using triethyl amine as the base and
dichloromethane as the solvent at temperatures ranging
from 0°C to room temperature. FT-IR was used to
monitor the progress of the reaction. The disappear-
We want to take advantage of a current focus in
organic chemistry, the extension of principles of organic
Scheme 1.
Keywords: solid-phase; N-unsubstituted b-lactams.
* Corresponding author. E-mail: bbanik@mail.mdanderson.org
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02236-0

9446
S. K. Dasgupta, B. K. Banik / Tetrahedron Letters 43 (2002) 9445–9447
ance of the imines peaks indicated the completion of
the reaction. Finally, rink resin was cleaved by using
50% trifluoroacetic acid in dichloromethane, and the
product, N-unsubstituted b-lactam, was isolated in
excellent yield (Scheme 1).13
N-unsubstituted b-lactam. Owing to the smooth and
excellent yield, this method has broad applicability. In
addition, resin-bound b-lactams can serve as intermedi-
ates for the synthesis of various other natural and
non-natural compounds. That is, the resin attached to
the nitrogen of the b-lactam ring can actually act as a
novel protective group during these transformations.
Application of the rink resin and other solid-support
mediated approaches toward the synthesis of b-lactam
and other compounds will be reported in due course.
Notably, a number of groups (acetoxy, phthalimido,
ether, ester and the ring itself) remained intact during
the acid treatment. The stereochemistry of the products
followed earlier observation (Table 1).
Considering the solid-supported reaction, excess
reagent was used in each step to assure complete con-
version, and so, the yield of the final product was high.
Excess reagents were removed by simply washing the
resin with polar solvents (dichloromethane or
methanol).
Acknowledgements
We gratefully acknowledge the funding support
received for this research project from the University of
Texas M.D. Anderson Cancer Center for the partial
support of this research. We are thankful to NIH
Cancer Center Support Grant, 5-P30-CA16672-25, in
particular the shared resources of the Pharmacology
and Analytical Center Facility.
In conclusion, we have demonstrated for the first time
that rink resin-derived imines can be used in a cycload-
dition reaction with acid chlorides (or equivalent) and
the resin bound b-lactam can be easily cleaved to the
Table 1. Preparation of N-unsubstituted b-lactams

S. K. Dasgupta, B. K. Banik / Tetrahedron Letters 43 (2002) 9445–9447
9447
8. Ruhland, B.; Bhandari, A.; Gordon, E. M.; Gallop, M.
A. J. Am. Chem. Soc. 1996, 118, 253.
References
9. Fitch, W. L.; Detre, G.; Holmes, C. P.; Shoolery, J. N.;
1. For a recent example, see: Bose, A. K.; Manhas, M. S.;
Banik, B. K.; Srirajan, V. In The Amide Linkage: Selected
Structural Aspects in Chemistry, Biochemistry, and Mate-
rial Science; Greenberg, A.; Breneman, C. M.; Liebman,
J. F., Eds.; Wiley-Interscience: New York, 2000; Chapter
7, p. 157 (b-Lactams: cyclic amides of distinction).
2. (a) Kant, J.; Walker, D. G. In The Organic Chemistry of
i-Lactams; Georg, G. I., Ed.; 1993; p. 121; (b) Durck-
heimer, W.; Blumbach, J.; Lattrell, R.; Scheunemann, K.
H. Angew Chem., Int. Ed. Engl. 1985, 24, 180; (c) O’Sulli-
van, J.; Abraham, E. P. In Antibiotics; Corocoran, J. W.,
Ed.; Springer: Berlin, 1981; Vol. 4; (d) Cooper, R. D. G.
In Topics in Antibiotics Chemistry; Sammes, P. G.; Hor-
wood, E., Eds.; Chichester, 1980; Vol. 3.
Keifer, P. A. J. Org. Chem. 1994, 59, 7955.
10. (a) Ghatak, A.; Becker, F. F.; Banik, B. K. Heterocycles
2000, 53, 2769; (b) Banik, B. K.; Ghatak, A.; Becker, F.
F. J. Chem. Soc., Perkin Trans 1 2000, 14, 2179; (c)
Banik, B. K.; Becker, F. F. Tetrahedron Lett. 2000, 41,
6551; (d) Ng, S.; Banik, I.; Okawa, A.; Becker, F. F.;
Banik, B. K. J. Chem. Res. 2001, 118.
11. Du, X.; Armstrong, R. W. J. Org. Chem. 1997, 62, 5678
and references cited therein.
12. Staudinger, H. Liebigs Ann. Chem. 1907, 356, 51.
13. A general experimental condition is given below: The
rink amide resin (loading 0.71 mmol/g) was deblocked by
using 20% piperidine/DMF. The polymer bound imines 3
were prepared by condensing the carbonyl compounds 2
with rink amine 1 and trimethyl orthoformate. To the
3. Suffness, M. Taxol Science and Applications; CRC Press:
Boca Raton, FL, USA, 1995.
4. Kronenthal, D. K.; Han, C. Y.; Taylor, M. K. J. Org.
Chem. 1982, 47, 2765.
polymer-bound imine
3 (100 mg) was added dry
dichloromethane (4 mL) and triethyl amine (6 equiv.).
The suspension was cooled to 0°C and to it was added
dropwise a solution of the acid chloride (3 equiv.) in
dichloromethane (1 mL). The mixture was stirred
overnight at room temperature. The resin was then
filtered and washed with dichloromethane (20 mL) and
dried. The b-lactam bound resin 4 was stirred in 50%
TFA/CH2Cl2 for 1 h, and the mixture was neutralized by
adding saturated sodium bicarbonate solution and
filtered. The resin was washed several times with
dichloromethane. The organic layer was separated and
washed with brine and dried over anhydrous sodium
sulfate. The b-lactam 5 (90% pure) was obtained by
evaporating the solvent. The crude b-lactam 5 was
purified by passing through a small florisil column (1 gm)
using ethyl acetate–hexanes (1:1) as the solvent. Com-
pounds (Table 1, entries 1–8 and 13–14) were character-
ized by a direct comparison with authentic samples
prepared by following a literature method4 (mp, IR and
NMR spectra). The other compounds (Table 1, entries
9–12) gave a comparable analytical data.
5. Alcaide, B.; Perez-Castells, J. P.; Sanchez-Vigo, B.;
Sierra, M. A. J. Chem. Soc., Chem. Commun. 1994, 587.
6. (a) DiPietro, D.; Borzilleri, R. M.; Weinreb, S. M. J. Org.
Chem. 1994, 59, 5856; (b) Boger, D. L.; Myers, J. B., Jr.
J. Org. Chem. 1991, 56, 5385; (c) Georg, G. I.; He, P.;
Kant, J.; Mudd, J. Tetrahedron Lett. 1990, 31, 451; (d)
Lasarte, J.; Palomo, C.; Picard, J. P.; Dunogues, J.;
Aizupurua, J. M. J. Chem. Soc., Chem. Commun. 1989,
72; (e) Arrieta, A.; Lecea, B.; Palomo, C. J. Chem. Soc.,
Perkin Trans 1 1987, 845; (f) Colvin, E. W.; McGarry, D.
G. J. Chem. Soc., Chem. Commun. 1985, 539; (g)
Fukuyama, T.; Laird, A. A.; Schmidt, C. A. Tetrahedron
Lett. 1984, 25, 4709; (h) Bose, A. K.; Manhas, M. S.;
Vincent, J. E.; Gala, K.; Fernandez, I. F. J. Org. Chem.
1982, 47, 4075.
7. (a) Mata, E. G. Cur. Pharm. Design 1999, 5, 955; (b)
Furman, B.; Thurmer, R.; Kaluza, Z.; Lysek, R.; Voelter,
W.; Chmielewski, M. Angew. Chem., Int. Ed. 1999, 38,
1121.