Solid-phase synthesis of beta-lactams via the ester enolate-imine condensation route.

Article abstract of DOI:10.1021/ol0055465

The ester enolate-imine condensation route to beta-lactams via an immobilized ester enolate has been achieved for the first time. The key reaction in the synthesis is the cyclization of the resin bound ester dianion and an imine. Traceless cleavage from the T1-triazene linker system yields the desired beta-lactams.

Full text of DOI:10.1021/ol0055465

ORGANIC
LETTERS
2
000
Vol. 2, No. 7
07-910
Solid-Phase Synthesis of â-Lactams via
the Ester Enolate−Imine Condensation
Route
9
Stefan Schunk and Dieter Enders*
Institut f u¨ r Organische Chemie, Rheinisch-Westf a¨ lische Technische Hochschule,
Professor-Pirlet-Strasse 1, 52074 Aachen, Germany
enders@rwth-aachen.de
Received January 13, 2000
ABSTRACT
The ester enolate−imine condensation route to â-lactams via an immobilized ester enolate has been achieved for the first time. The key
reaction in the synthesis is the cyclization of the resin bound ester dianion and an imine. Traceless cleavage from the T1-triazene linker
system yields the desired â-lactams.
â-Lactam-based antibiotics include penicillins, cephalospor-
ins, carbapenems, norcardins, and monobactams. These
report, to the best of our knowledge, the first ester enolate-
imine condensation route to â-lactams employing an im-
mobilized ester enolate.
1
compounds constitute a large class of broad-spectrum
antibiotics that effectively combat bacterial infections. Solid-
phase organic synthesis enables the preparation of large
numbers of structurally related molecules in short periods
of time, which is especially important for the optimization
of lead structures in the pharmaceutical industry. Despite
these facts, the solid-phase synthesis of â-lactams has not
been widely reported.2
The main reasons for choosing the T1-triazene linker
6
system to immobilize the ester were its stability in basic
(2) For solid-phase synthesis, see: (a) Ruhland, B.; Bhandari, A.; Gordon,
E. M.; Gallop, M. A. J. Am. Chem. Soc. 1996, 118, 253-254. (b) Pei, Y.;
Houghten, R. A.; Kiely, J. S. Tetrahedon Lett. 1997, 38, 3349-3352. (c)
Ruhland, B.; Bombrun, A.; Gallop, M. A. J. Org. Chem. 1997, 62, 7820-
7826. (d) Singh, R.; Nuss, J. M. Tetrahedon Lett. 1999, 40, 1249-1252.
For soluble-polymer-supported synthesis, see: (e) Annunziata, R.; Benaglia,
M.; Cinquini, M.; Cozzi, F. Chem. Eur. J. 2000, 6, 133-138. (f) Benaglia,
M.; Cinquini, M.; Cozzi, F. Tetrahedon Lett. 1999, 40, 2019-2020. (g)
Molteni, V.; Annunziata, R.; Cinquini, M.; Cozzi, F.; Benaglia, M.
Tetrahedon Lett. 1998, 39, 1257-1260. For the attatchment of preformed
â-lactams to various polymers, see: (h) Furman, B.; Th u¨ rmer, R.; Kałuza,
Z.; Voelter, W.; Chmielewski, M. Tetrahedon Lett. 1999, 40, 5909-5912.
The first preparation of a â-lactam was reported in 1907,
when Staudinger described the cycloaddition between ketenes
3
and imines. The Staudinger reaction has been immobilized
2a
by Ruhland et al. in 1996. In 1943 Gilman and Speeter
(
i) Furman, B.; Th u¨ rmer, R.; Kałuza, Z.; Łysek, R.; Voelter, W.;
developed a one-pot ester-imine condensation to yield
Chmielewski, M. Angew. Chem. 1999, 111, 1193-1195; Angew. Chem.,
4
â-lactams. Since this initial report, several research groups
Int. Ed. 1999, 38, 1121-1123. (j) Matta, E. G. Tetrahedon Lett. 1997, 38,
6
335-6338.
have investigated the reaction and established the condensa-
(
3) Staudinger, H. Liebigs Ann. Chem. 1907, 356, 51-123.
tion of ester enolates with imines as an important synthetic
(4) Gilman, H.; Speeter, H. J. J. Am. Chem. Soc. 1943, 65, 2255-2256.
5
methodology for the preparation of â-lactams. We now
(5) For reviews, see: (a) Hart, D. J.; Ha, D. C. Chem. ReV. 1989, 89,
447-1465. (b) Brown, M. J. Heterocycles 1989, 29, 2225-2244. (c)
1
Kleinman, E. F. In ComprehensiVe Organic Synthesis; Heathcock, C. H.,
Ed.; Pergamon Press: Oxford, 1991; Vol. 2, Chapter 4.1, pp 893-951.
(6) Br a¨ se, S.; Enders, D.; K o¨ bberling, J.; Avemaria, F. Angew. Chem.
1998, 110, 3614-3616; Angew. Chem., Int. Ed. 1998, 37, 3413-3415.
(
1) (a) Manhas, M. S.; Bose, A. K. â-Lactams: Natural and Synthetic;
Wiley: New York, 1971, Part 1. (b) Lednicer, D. The Organic Chemistry
of Drug Synthesis; Wiley: New York, 1995; Vol. 5.
1
0.1021/ol0055465 CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/11/2000

Several peptide-coupling reagents (e.g., 2-chloro-1-meth-
ylpyridinium iodide, N-ethyl-N′-[3-(dimethylamino)propyl]-
carbodiimid hydrochloride/1-hydroxybenzotriazol (EDC/
HOBt), and pentafluorophenyl diphenylphosphinate (FDPP))
were tested in the synthesis of resins 3 ( step b). Since all
coupling reagents gave the same results, 2-chloro-1-meth-
ylpyridinium iodide was used for convenience. Resin 3b
Scheme 1a
affords diazonium salt 4b after treatment with 5% TFA/CH
2
-
Cl . To obtain pure cleavage products 4, the triazene
2
formation reaction (step a) had to be carried out at room
temperature. Lower temperatures resulted in lower purity of
4
and lower loading of 3 (e.g., triazene formation at -10
°
C, 1 h w purity ) 75%, loading ) ∼80%).
Table 1 shows the results for the reaction sequence 1 f
4
(Scheme 1) with different R-substituted amino acid methyl
esters. The loading of resins 3a-3c and the purity of the
different diazonium salts 4a-4c were very good.9
The ester enolate-imine condensation was initially tested
in the liquid phase (Scheme 2) on model compound 5b. This
Scheme 2a
a
(
a) 1. 5 equiv of p-aminobenzoic acid, 10 equiv of BF
3
2
‚Et O,
t
1
1
0 equiv of BuONO, THF, -10 °C, 1 h; 2. 1, pyridine/DMF (1:
), rt, 1 h; (b) 2, 3 equiv of amino acid methyl ester‚HCl, 2 equiv
of 2-chloro-1-methylpyridinium iodide, 20 equiv of NEt
rt, 12 h; (c) 5% TFA/CH Cl
3 2 2
, CH Cl ,
2
2
.
media and the possibility of introducing a variety of
7
functionalities by applying different cleavage procedures.
A simple three-step procedure (Scheme 1) starting from
benzylamine resin 1 via 2 gave ester resins 3 with high
loading and excellent purity of the corresponding cleavage
products 4 (Table 1).
a
(
a) 1. 2.2 equiv of LiHMDS, THF, -78 °C, 20 min; 2. 1 equiv
of PhCHdNPh, -78 °C to rt, 23 h; 3. H
2
O.
Table 1. Preparation of Ester Resins 3 and Diazonium Salts 4
reaction gave â-lactam 6b in 71% yield and de g 96%.10
The relative configuration of 6b was determined by NOE
experiments to be trans. The cyclization reaction with
compound 5a afforded, not surprisingly, only complex
product mixtures which were not further investigated.11
LiHMDS was found to give best results for dianion genera-
tion.
3
, 4
R1
loading (3)a
purity (4)b
a
b
c
H
Me
Ph
94%
97%
98%
g96%
95%
94%
a
Resins identified by IR spectroscopy. Loading of resins 3 determined
b
by nitrogen elemental analysis. Purity of diazonium salts 4 determined
1
by H NMR spectroscopy (solvent: d4-MeOH).
(9) Typical procedure: All reactions were carried out in absolute solvents
under an argon atmosphere. p-Aminobenzoic acid (16 mmol) was dissolved
in 50 mL of THF and cooled to -10 °C; BF3‚Et2O (32 mmol) and tert-
butyl nitrite (32 mmol) were added. The reaction mixture was stirred at
-10 °C for 1 h and then diluted with 25 mL of pyridine and 25 mL of
DMF. Benzylamine resin 1 (3.2 mmol) was added and the resulting mixture
stirred at rt for 1 h. The resin was washed with pyridine/DMF, THF/NEt3,
Treatment of 1 with 4-carboxybenzenediazonium tet-
rafluoroborate yielded T1-benzoic acid resin 2. This reaction
has to proceed under basic conditions, but only pyridine and
lutidine were found to be reasonable bases. Other bases, e.g.,
triethylamine, H u¨ nig’s base, DMAP, and BuOK, resulted
in decomposition of the diazonium salt. Standard conditions
and MeOH/NEt . Resin 2 (3.2 mmol) and 2-chloro-1-methylpyridinium
3
t
iodide (6.4 mmol) were suspended in 80 mL of CH Cl , before 20 equiv of
2
2
NEt3 was added. Alanine methyl ester hydrochloride (9.6 mmol) was added
after 15 min. The resulting mixture was stirred overnight at rt. The resin
was washed with THF, Et2O, and MeOH. Resin 3 was collected in a glass
pipet and suspended in 5% TFA/CH2Cl2. The acidic solution was filtered
from the resin after 1 min. This procedure was repeated three times to yield
are applied for the diazotation of p-aminobenzoic acid with
tert-butyl nitrite.8
4
.
(
7) (a) Br a¨ se, S.; Schroen, M. Angew. Chem. 1999, 111, 1139-1142;
(10) Reaction conditions were not optimized.
(11) Low yields of R-unsubstituted esters in ester enolate-imine
Angew. Chem., Int. Ed. 1999, 38, 1071-1073. (b) Br a¨ se, S.; Dahmen, S.
In press.
condensation reactions have been described in the literature, see e.g., ref
5a.
(8) Colas, C.; Goeldner, M. Eur. J. Org. Chem. 1999, 1357-1366.
908
Org. Lett., Vol. 2, No. 7, 2000

The liquid-phase reaction conditions were transferred to
the solid phase (Scheme 3) without any problems. It is most
During the investigations on diazonium salts, we found
out that they can easily be transformed into deuteriomethoxy-
substituted products. Surprisingly, changing d -MeOH to
4
12
1
4
MeOH does not yield the methoxy-substituted products but
instead traceless products. To yield methoxy-substituted
Scheme 3a
4
products, reaction conditions had to be altered from d -
MeOH, rt, 48 h to MeOH, 5% TFA, 60 °C, 30 min. Traceless
cleavage with methanol could not be applied to a wide range
of resins, because in most cases products were mixtures of
1
5
methoxy and traceless compounds. Since these mixtures
could only be purified by column chromatography, we
decided to investigate other methods.
The best conditions for traceless cleavage turned out to
1
6
be modified Keumi conditions (2-fluorenediazonium tet-
rafluoroborate, 1,2 equiv of chlorotrimethylsilane, THF/DMF
(
5/3), 60 °C, 60 min). Optimized conditions for diazonium
a
(
a) 1. 2,2 equiv of LiHMDS, THF, -78 °C, 1,5 h; 2. 3 equiv
salt 4a were THF/DMF (5/2), rt, 12 h. These conditions,
applied to diazonium salt 8a, lead to the formation of
intensely colored side products. Changing reaction conditions
to THF/DMF (5/2), 60 °C, 15 min gave the best results for
lactam resins and very good results for resins 4. Purity of
traceless compounds by GC/MS are as follows: 4a (94%),
2
2
of R CHdNPh, -78 °C to rt, 23 h; 3. H O.
probable that the reaction proceeds, as in liquid phase, via a
dianion.13
The condensation reaction of 3b was carried out with a
range of imines, which all gave very good results concerning
loading of the lactam resin 7 and purity of the cleaved
diazonium salt 8 (Scheme 4).
4
b (91%), 4c (93%). Lactams 9 were easily separated from
yellow byproducts by dissolving them in EtOAc/pentane (40:
0) and eluting them through 7 cm SiO . Results achieved
6
2
using this procedure are shown in Table 2.
Scheme 4a
Table 2. Preparation of â-Lactams 9
a
2 2
(a) 5% TFA/CH Cl ; (b) THF/DMF (5/2), 60 °C, 15 min.
The diazonium salts were reasonably stable at room
1
temperature and could be analyzed by H NMR spectroscopy
4
in d -MeOH.
Several procedures to transform the diazonium salts into
traceless products had to be tested before formation of pure
â-lactams could be achieved. All methods were first tested
on resin 3a and then further optimized on resin 7a.
Conditions published to date for traceless cleavage from a
T1-triazene linker resulted in decomposition of the sensitive
a
Resins identified by IR spectroscopy. Loading of resin 7 determined
by nitrogen elemental analysis. b Compounds 9 identified by 1H/13C NMR
spectroscopy and MS. Purity of compounds 9 determined by HPLC. Yields
c
6
of â-lactams 9 after six steps based on theoretical loading of Merrifield
resin. d de determined by C NMR spectroscopy.
13
â-lactams.
Org. Lett., Vol. 2, No. 7, 2000
909

Eight different â-lactams 9 were prepared in high purity,
excellent diastereoselectivity, and good yields. No change
in diastereomeric purity could be observed by comparing
trans configuration. This is the same configuration as found
in solution-phase synthesis of 9a.
1
7
In conclusion, the first solid-phase synthesis of â-lactams
via ester enolate-imine condensation employing an im-
mobilized ester enolate has been developed. The substrates
were attatched to the polymer with a T1-triazene linker,
which was cleaved traceless.
1
the H NMR spectra of compounds 8 and 9. The relative
configuration of â-lactams 9c, 9e, 9g, and 9h was determined
by NOE experiments to be trans. Assuming a uniform
reaction pathway, we assign compounds 9a-h as having the
We are currently employing the established synthesis for
the preparation of highly diverse â-lactam libraries.
(
12) Typical procedure: LiHMDS was added to resin 7 (0, 96 mmol)
in 25 mL of THF at -78 °C and the resulting mixture was stirred for 1.5
h. After addition of the imine (2.88 mmol), the reaction mixture was warmed
from -78 to 0 °C within 16 h and then stirred at rt for 7 h. Lactam resin
Acknowledgment. We thank Dr. J. Runsink for carrying
out the NOE investigations. This work was supported by
the Deutsche Forschungsgemeinschaft (Graduiertenkolleg
Stipendium to S.S.) and the Fonds der Chemischen Industrie.
We thank Calbiochem Novabiochem AG, Degussa-H u¨ ls AG,
BASF AG, the former Hoechst AG, Bayer AG, and Wacker
Chemie for the donation of chemicals.
7
was washed with THF, Et2O, and MeOH. Resin 7 was collected in a
glass pipet and suspended in 5% TFA/CH2Cl2. The acidic solution was
filtered from the resin after 1 min. This procedure was repeated three times
to yield 10. Diazonium salt 10 obtained by cleavage from 100 mg of resin
was dissolved in 4 mL of THF/DMF (5/2) and heated to 60 °C for 15
min. Pure â-lactams were obtained by evaporating the solvent and elution
of the crude product over 7 cm of SiO2.
7
(
13) Overman, L. E.; Osawa, T. J. Am. Chem. Soc. 1985, 107, 1698-
1
6
701.
(
(
14) Reaction conditions: d4-MeOH, rt, 48 h.
15) Broxton, T. J.; Bunnett, J. F.; Paik, C. H. J. Org. Chem. 1977, 42,
OL0055465
43-649.
16) Keumi, T.; Umeda, T.; Inoue, Y.; Kitajima, H. Bull. Chem. Soc.
Jpn. 1989, 62, 89-95.
(
(17) Gluchowski, C.; Cooper, L.; Breigbreiter, D. E.; Newcomb, M. J.
Org. Chem. 1980, 45, 3413-3416.
910
Org. Lett., Vol. 2, No. 7, 2000