A new polymer-supported reagent for the synthesis of β-lactams in solution

Article abstract of DOI:10.1021/jo048400i

A modified Mukaiyama reagent was prepared on a PS-DVB resin. This reagent was used for the preparation of β-lactams, using the Staudinger reaction. The products were obtained by generating the ketene from a carboxylic acid under sonication with the resin followed by reaction with the imine. Excess of the imine was removed by reduction followed by acid scavenging.

Full text of DOI:10.1021/jo048400i

A New Polymer-Supported Reagent for the
SCHEME 1
Synthesis of â-Lactams in Solution
†
†
Donato Donati, Costanza Morelli,
‡
,†
Andrea Porcheddu, and Maurizio Taddei*
Dipartimento di Chimica, Universit a` degli Studi di Sassari,
Via Vienna 2, 07100, Sassari, Italy, and Dipartimento di
Chimica e Dipartimento Farmaco Chimico Tecnologico,
Universit a` degli Studi di Siena, Via A. Moro,
5
3100 Siena, Italy
Following our interest in â-lactam and polymer-sup-
ported syntheses, we were attracted by the possibility
6
taddei.m@unisi.it
of preparing â-lactams using polymer-supported re-
agents. This would be the starting point for the produc-
tion of libraries of compounds for biological screening. We
now report, to the best of our knowledge, the first
example of the synthesis of â-lactams in solution using
the Staudinger reaction promoted by a polymer-sup-
ported Mukaiyama-type reagent. One of the most popular
approaches to the preparation of â-lactams is, in fact, the
Received September 10, 2004
Abstract: A modified Mukaiyama reagent was prepared
on a PS-DVB resin. This reagent was used for the prepara-
tion of â-lactams, using the Staudinger reaction. The prod-
ucts were obtained by generating the ketene from a carbox-
ylic acid under sonication with the resin followed by reaction
with the imine. Excess of the imine was removed by
reduction followed by acid scavenging.
Staudinger reaction, the cycloaddition between a ketene
and an imine.7 The ketene is generated by a base-
mediated elimination of an acyl chloride or another
activated carboxylic acid derivative. 2-Chloro-1-meth-
ylpyridinium iodide (the Mukaiyama reagent) is one of
Recently polymer-supported reagents have received
considerable interest with the growth of high throughput
solution phase synthesis. This approach allows for the
preparation of arrays of compounds by using reactions
that are often clear, that can be monitored with standard
analytical techniques, and that should give the products
with simple filtration and evaporation of the solvents.
Although polymer-supported reagents have been de-
scribed for many transformations, there is still a need
for new reagents that would give access to additional
classes of compounds.
The â-lactam ring is the key component of commonly
used antibiotics as penicillins, cephalosporins, carba-
penems, and monobactams and is present in several
peptidomimetics with interesting activities as protease
8
the most effective reagents for this activation. Conse-
1
quently, we decided to investigate the possibility of
immobilizing a 2-chloropyridinium salt on a polymer by
evaluating its reaction with carboxylic acids and imines.
A potentially straightforward approach was the alkyla-
tion of 2-chloropyridine with a Merrifield resin (Scheme
1
). This reaction was carried out in toluene at 110 °C for
2
36 h and the product 1a was obtained after filtration of
the solvent. Compound 1a was mixed with phenoxyacetic
acid in the presence of Et N and after 2 h at 40 °C,
3
N-benzyliden(phenyl)methanamine (obtained from benz-
aldehyde and benzylamine in the presence of trimethyl-
9
orthoformate) was added, but no reaction was observed.
We tried a variety of reaction conditions, but never
observed the formation of the desired â-lactam via either
the chloride 1a or the iodide 1b.10
3
inhibitors. Despite their importance, relatively few
examples of â-lactam synthesis on the solid phase have
been reported recently4 and no example of polymer-
assisted preparation of â-lactams in solution has been
(
4) Reviews: Mata, E. G. Curr. Pharm. Design 1999, 5, 955. Rafai
5
described.
Far, A. Angew. Chem., Int. Ed. 2003, 42, 2340. (a) Reger, T. S.; Janda,
K. D. Bioorg. Med. Chem. 2002, 12, 837. (b) Lysek, R.; Furman, B.;
Cierpucha, M.; Grzeszczyk, B.; Matyjasek, L.; Chmielewski, M. Eur.
J. Org. Chem. 2002, 2377. (c) Wills, A. J.; Krishnan-Ghosh, Y.;
Balasubramanian, S. J. Org. Chem. 2002, 67, 8034. (d) Schunk, S.;
Enders, D. J. Org. Chem. 2002, 67, 8034. (e) Dasgupta, S. K.; Banik,
B. K. Tetrahedron Lett. 2002, 43, 9445. (f) Delpiccolo, C. M. L.; Fraga,
M. A.; Mata, E. G. J. Comb. Chem. 2003, 5, 208. (g) Delpiccolo, C. M.
L.; Mata, E. G. Tetrahedron Lett. 2004, 45, 4085.
‡
Universit a` degli Studi di Sassari.
†
Universit a` degli Studi di Siena.
(
1) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.; Leach,
A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.; Storer, R. I.; Taylor, S.
J. J. Chem. Soc., Perkin Trans. 1 2000, 3815. Kirschning, A.; Monen-
schein, H.; Wittemberg, R. Angew. Chem., Int. Ed. Engl. 2001, 40, 650.
Flynn, D. L.; Berk, S. C.; Makara, G. M. Curr. Opin. Drug Discovery
Dev. 2002, 5, 580. Ley, S. V.; Baxendale, I. R. Nat. Rev. Drug. Discovery
(5) A column catalytic process for asymmetric synthesis of â-lactams
has been described. Hafez, A. M.; Taggi, A. E.; Wack, H.; Drury, W.,
III; Lectka, T. Org. Lett. 2000, 2, 3963. France, S.; Wack, H.; Hafez,
A. M.; Taggi, A. E.; Witsil, D. R.; Lectka, T. Org. Lett. 2002, 4, 1603.
Hafez, A. M.; Taggi, A. E.; Dudding, T.; Lectka, T. J. Am. Chem. Soc.
2001, 123, 10853.
(6) Meloni, M. M.; Taddei, M. Org. Lett. 2001, 3, 337. De Luca, L.;
Giacomelli, G.; Porcu, G.; Taddei, M. Org. Lett. 2001, 3, 855.
(7) Georg, G. I.; Mashava, P. M.; Guan, X. Tetrahedron Lett. 1991,
32, 581.
2
002, 1, 573.
(
(
2) Janda, K., Ed. Bioorg. Med. Chem. Lett. 2002, 12, issue 14.
3) The Organic Chemistry of Beta-Lactams; Georg, G. I., Ed.;
VCH: New York, 1993. Yoakim, C.; Ogilvie, W. W.; Cameron, D. R.;
Chabot, C.; Guse, I.; Hach e´ , B.; Naud, J.; O’Meara, J. A.; Plante, R.;
D e´ ziel, R. J. Med. Chem. 1998, 41, 2882. Linder, M. R.; Podlech, J.
Org. Lett. 1999, 1, 869. Abell, A. D.; Gardiner, J. J. Org. Chem. 1999,
6
4, 9668. Palomo, C.; Aizpurua, J. M.; Benito, A.; Galarza, R.; Khamrai,
U.K.; Vasquez, J.; de Pascual-Teresa, B.; Nieto, P. M.; Linden, A.
Angew. Chem., Int. Ed. Engl. 1999, 38, 3056. Setti, E. L.; Davis, D.;
Chung, T.; McCarter, J. Bioorg. Med. Chem. Lett. 2003, 13, 2051.
Banik, I.; Becker, F. F.; Banik, B. K. J. Med. Chem. 2003, 46, 12.
(8) Huang, H.; Iwasawa, N.; Mukaiyama, T. Chem. Lett. 1984, 1465.
Amin, S. G.; Glazer, R. D.; Manhas, M. S. Synthesis 1979, 210.
(9) Look, G. C.; Murphy, M. M.; Campbell, D. A.; Gallop, M. A.
Tetrahedron Lett. 1995, 36, 2937.
10.1021/jo048400i CCC: $27.50 © 2004 American Chemical Society
9316
J. Org. Chem. 2004, 69, 9316-9318
Published on Web 11/13/2004

SCHEME 2a
SCHEME 3
a
Reagents and conditions: (a) N-Boc-6-aminocaproic acid,
Cs2CO3, DMF, 80 °C, 3 days. (b) TFA, CH2Cl2.( c) 6-Chloronico-
tinoyl chloride in CH2Cl2/DIPEA. (d) MeI 75 °C, 2 h. (e) d-TFA
neat, 70 °C, 2 h.
We hypothesized that, probably, the reactive center
was too close to the resin surface to efficiently react with
the carboxylic acid, so we decided to introduce a spacer,
changing the architecture of the reagent (Scheme 2).
Thus, N-Boc-6-aminocaproic acid was linked to a Merri-
field resin under standard conditions (Cs
2 3
CO , DMF, 80
a
b
c
Cis isomer. Trans isomer. Cis/trans mixture 3:1.
°
C, 3 days, 96% yield). Compound 2 was deprotected at
the nitrogen with TFA and the loading determined with
Following standard conditions (generation of the ketene
from the acid, the pyridinium salt, and a tertiary amine
in boiling CH Cl followed by addition of the imine) the
2 2
a quantitative ninhydrin test.11
The resin-bound amine was coupled with 6-chloroni-
1
2
2 2
cotinoyl chloride in CH Cl /DIPEA. The reaction was
expected â-lactam was recovered in very low yields.
11
very rapid (negative Kaiser test) and compound 3 was
obtained in high yield. On this resin, we tried different
procedures for alkylation. When mild conditions were
used, compound 4 was obtained in low yield. Heating for
long times produced a dark resin where no traces of the
expected product were found. Finally, a correct protocol
arose from heating the resin at 80 °C in MeI in a sealed
tube for no more than 2 h. After washing with dry
dichloromethane,13 and drying the resin, the structure
Better results were obtained by mixing all the reagents
together in dry CH Cl in a sealed vial placed into an
2 2
ultrasound bath for 2 h. Filtration on a short path of silica
gel, followed by evaporation of the solvent, gave the
â-lactam 5 together with unreacted imine. We tried to
use a stoichiometric amount of the imine to prevent the
contamination of the crude product with the excess of the
imine but the yield was very low.
Obliged to use 2 equiv of imine, we looked for a
scavenger. We did not find any example of scavenging of
imine in the literature. Consequently, we decided to
14
of product 4 was determined by cleavage from hot TFA.
1
H NMR analysis confirmed the molecular structure and
the mass spectrum, showing a single peak at m/z 377,
suggested the formation of the 2-iodopyridinium salt.15
The presence of the second atom of iodine (as the anion)
was confirmed by microanalysis.16 Starting from a Mer-
rifield resin loading of 1.6 mmol/g, we obtained a resin
with about 1.2-1.0 mmol/g of product determined through
the N contents obtained by microanalysis (87-75% yield).
Again, we tried the reaction between phenoxyacetic
acid and the aldimine to test our supported reagent.
4
reduce the excess of the imine with NaBH or macroporous
1
7
triethylammomium methylpolystyrene borohydride to
give the corresponding dibenzylamine. After filtration
and evaporation of the solvent, the amine was removed
through filtration over silica gel or SCX columns. After
this protocol, â-lactam 5 was isolated in 60% yield with
a good level of purity (80-85% at 1H NMR, see the
Supporting Information).
1
Nevertheless, we observed in the H NMR spectrum a
singlet at δ 4.45 that was finally attributed to N-
benzylphenoxyacetamide, a byproduct previously ob-
served in Staudinger reactions.4 The formation of this
product was avoided changing again the order of addition.
(
10) During the writing of this paper, the preparation of compound
b was described together with its use for the synthesis of carbodi-
imides: Convers, E.; Tye, H.; Whittaker, M. Tetrahedron Lett. 2004,
5, 3401.
1
f
4
(
11) For the qualitative and quantitative colorimetric tests used
Phenoxyacetic acid was mixed with resin 4 in dry CH
2
-
through this paper see: Gaggini, F.; Porcheddu, A.; Reginato, G.;
Cl in the presence of Et N and the vial placed in an
2
3
Rodriquez, M.; Taddei, M. J. Comb. Chem. 2004, 6, 805.
18
(
(
12) Commercially available from Aldrich.
13) Warning: washing the resin with dry DMF gave lower yields
ultrasound bath for 2 h. To this mixture was added the
imine and the reaction mixture was heated at 70 °C
of 4.
4
overnight. The solvent evaporated and NaBH in EtOH
added at room temperature. After 10 min of stirring, the
(
14) An analogous MW assisted cleavage from Merrifield resin has
been previously reported: Stadler A.; Kappe, C. O. Eur. J. Org. Chem.
2
001, 919.
(
15) This exchange reaction of R-halogenated pyridines has been
previously described: Bradlow, H. L.; Vanderwerf, C. A. J. Org. Chem.
951, 16, 1143.
(17) We obtained successful results exclusively using supported
borohydride purchased from Argonaut.
(18) The use of ultrasounds allowed the formation of 5 in yield higher
than with conventional heating, probably for a more efficient motion
of the beads.
1
(
16) The percentage of C, H, and N found was correct exclusively
inserting a second iodine atom in the structure. See the Supporting
Information.
J. Org. Chem, Vol. 69, No. 26, 2004 9317

solvent was evaporated and the residue passed through
an SCX column to remove the amine.19 Evaporation of
the solvent gave â-lactam 5 (as a single cis isomer)
without traditional column chromatography, as generally
required to separate the byproducts of Mukaiyama
reagent from the desired â-lactam.
To explore the general applicability of the Mukaiyama
solid supported reagent, we examined the preparation
of diverse â-lactams, as reported in Scheme 3. Results
2 3
acid (2.1 g, 9.6 mmol) was added to a solution of Cs CO (3.2 g,
9.6 mmol) in dry DMF (120 mL), followed by addition of the
Merrifield resin (chloride form, 2 g, 3.2 mmol). The mixture was
heated at 80 °C for 72 h in a rotatory apparatus. The beads were
collected on a glass filter and washed with DMF (5 mL), a 20%
solution of TFA in CH
2
Cl
2
(2 × 5 mL), DMF (3 × 5 mL), and
CH Cl (4 × 5 mL). Then, the beads were treated with 1/1 TFA/
2
2
CH
2
Cl
2
solution (3 × 20 min) at room temperature. The reaction
completion was monitored by the Kaiser test. The beads were
washed with DMF (3 × 5 mL) and CH Cl (5 × 5 mL) and dried
at 60 °C under vacuum under P to give resin 2 (3.1 g).
2
2
2 5
O
were always satisfactory in terms of yield and purity
Microanalysis: C, 74.80; H, 6.87; N, 1.39 corresponding to a
loading of 1.22 mmol/g of resin (96% yield).
1
(
higher than 90% at H NMR analysis). Compounds 6-13
were obtained as a single isomer or as a mixture of cis/
trans isomers depending on the substituents, as observed
in the homogeneous phase.20
Synthesis of Supported Reagent 4. Resin 2 (1 g, 1.2 mmol)
was suspended in dry CH Cl (5 mL), followed by addition of
2
2
3
6-chloronicotinoyl chloride (790 mg, 4.8 mmol) and Et N (2 mL).
The mixture was shaken for 10 min at room temperature, and
then washed with CH Cl
(2 × 5 mL), DMF (3 × 5 mL), and
CH Cl
(4 × 5 mL). The reaction completion was monitored with
a negative Kaiser test. The beads were collected in a vial, MeI
3 mL) was added, and the sealed vial was heated at 80 °C for
2 h (oil bath). After cooling, the beads were collected on a glass
filter and successively washed with CH Cl
(5 × 5 mL) and dried
at 60 °C under vacuum and in the presence of P to give the
In conclusion we have prepared an efficient polymer-
21
2
2
supported Mukaiyama-type reagent that was suitable
for the generation of ketenes for Staudinger cycloaddition
with imines. In addition, we also developed a protocol
for the scavenging of imines and for the isolation of pure
â-lactams that can be easily applied to a parallel syn-
thesis.
2
2
(
2
2
2 5
O
supported reagent 4. The identity of the product loaded on the
resin was monitored by d-TFA assisted cleavage. Thus, 10 mg
of dry beads was placed into a NMR tube with neat d-TFA (0.8
mL) and the tube was heated at 70 °C (oil bath) for 2 h. After
cooling, the spectrum of the cleaved compound was directly
Experimental Section
6-(tert-Butoxycarbonylamino)caproic Acid. Di-tert-bu-
toxycarbonate (24 g, 0.11 mol) was dissolved in 200 mL of THF.
The mixture was added dropwise into a solution of 6-aminocap-
roic acid (13.2 g, 0.1 mol) in NaOH (0.5 M, 220 mL) at 0 °C and
the resulting mixture was stirred for 6 h at room temperature.
The reaction mixture was quenched with water (100 mL), and
the whole mixture was extracted with ether (3 × 200 mL). The
aqueous layer was acidified at pH 5 with a buffered solution of
sodium citrate/HCl (pH 2-3) at 0 °C, then extracted with ether
1
recorded. H NMR and mass (ESI) spectra derived from resin 4
are reported in the Supporting Information. Microanalysis of
resin 4: C, 63.15; H, 5.58; N, 2.28, corresponding to a loading of
0
.91 mmol/g of resin (98% yield). These data fit exclusively with
the presence of two iodine atoms on the resin.
General Procedure for the Syntesis of â-Lactams with
Use of Supported Reagent 4: 1-Benzyl-3-phenoxy-4-phen-
yl-2-azetidinone, 5. Supported reagent 4 (200 mg, 0.2 mmol),
phenoxyacetic acid (15 mg, 0.1 mmol), and triethylamine (55 µL,
(
4 × 400 mL), dried over MgSO
4
, and filtered, then the solvent
was evaporated to give a crude oil, which was cooled at -20 °C.
Petroleum spirit was added at -20 °C to give the product as
0
.4 mmol) in CH
heated at 60 °C inside an ultrasound bath. Then, benzyliden-
phenyl)methanamine (0.2 mmol) was added and the mixture
2 2
Cl (2 mL) were mixed in a sealed vial and
22
colorless fine needles (19.3 g, 88%). Mp 31-32 °C (lit. mp 32.5-
(
3
3.5 °C).
was heated at 70 °C (oil bath) for an additional 14 h. After
evaporation of the solvent under reduced pressure, ethanol was
added (3 mL), followed by addition of NaBH (16 mg, 0.4 mmol).
4
Linkage of 6-(tert-Butoxycarbonylamino)caproic Acid
on Merrifield Resin 2. 6-(tert-Butoxycarbonylamino)caproic
The mixture was shaken for 10 min, the solvent evaporated, and
the residue passed through an SCX-3 cartridge (International
(
19) Filtration through the SCX column also removed the alkylam-
monium and boron salts byproducts. To elute the required â-lactam,
petroleum ether was used. Alternatively, the amine can be scavenged
with chlorosulfonate polystyrene and (N,N-diisopropylaminomethyl)-
polystyrene and the solution passed through a short path of silica to
remove salts.
2 2
Sorbent Technology, IST) with CH Cl and petroleum ether as
the solvents. Removal of the solvent under reduced pressure
1
gives the crude â-lactam 5 (21 mg, 65% yield). H NMR and mass
(ESI) spectra are reported in the Supporting Information.
(
20) The mechanism of â-lactam formation has been investigated
â-Lactams 5-13 were prepared following this general proce-
extensively. However, the rationale for the observed diastereoselectivity
and enantioselectivity remains unknown. It has been shown that the
stereoselectivity depends on a number of factors: the structure of the
imine, activated acid, sequence of reagent addition, solvent, temper-
ature, and bases. See, for example: (a) Arrieta, A.; Lecea, B.; Cossio,
F. P. J. Org. Chem. 1998, 63, 5869. (b) Cossio, F. P.; Arrieta, A.; Lecea,
B.; Ugalde, J. M. J. Am. Chem. Soc. 1994, 116, 2085. (c) Cossio, F. P.;
Ugalde, J. M.; Lopez, X.; Lecea, B.; Palomo, C. J. Am. Chem. Soc. 1993,
dure. The products were characterized through their melting
points (after crystallization or short column chromatography)
or comparison with reported spectroscopic data (see the Sup-
porting Information).
Acknowledgment. The work was financially sup-
ported by MIUR (Rome) as a project within PRIN-2002.
NikemResearch srl (Milan) is also acknowledged for
financial support.
1
15, 995. (d) Hegedus, L. S.; Montgomery, J.; Narukawa, Y.; Snustad,
D. C. J. Am. Chem. Soc. 1991, 113, 5784. (e) Lopez, R.; Sordo, T. L.;
Sordo, J. A.; Gonzalez, J. J. Org. Chem. 1993, 58, 7036. (f) Lynch, J.
E.; Riseman, S. M.; Laswell, W. L.; Tschaen, D. M.; Volante, R. P.;
Smith, G.; Shinkai, I. J. Org. Chem. 1989, 54, 3792. (g) Bose, A. K.;
Chiang, Y. H.; Manhas, M. S. Tetrahedron Lett. 1972, 13, 4091.
Supporting Information Available: Characterization of
4 and 5-13. This material is available free of charge via the
Internet at http://pubs.acs.org.
(
21) Reagent 4 eventually could be used for synthetic applications
typical of 2-chloro-1-methylpyridinium iodide. See: Mukaiyama, T.
Angew. Chem., Int. Ed. Engl. 1979, 18, 707.
(
22) Alam, Md. R.; Maeda, M.; Sasaki, S. Bioorg Med Chem. 2000,
8
465.
JO048400I
9318 J. Org. Chem., Vol. 69, No. 26, 2004