Synthesis of a dihydroxythiophene analogue of catechosporines

Article abstract of DOI:10.1016/S0960-894X(99)00697-6

A vinylogous cephalosporine bearing a dihydroxythiophene moiety as a potential catechol surrogate has been synthesised (I-e-β). Even if the anti staphylococcus spectrum displayed by this compound is of interest, its activity against Pseudomonas species, expected for such a structure, remains disappointing. (C) 2000 Elsevier Science Ltd. All rights reserved.

Full text of DOI:10.1016/S0960-894X(99)00697-6

Bioorganic & Medicinal Chemistry Letters 10 (2000) 349±352
Synthesis of a Dihydroxythiophene Analogue of Catechosporines
C. Dini* and J. Aszodi
Medicinal Chemistry Department, Hoechst Marion Roussel, France102 rte de Noisy 93235, Romainville Cedex, France
Received 13 September 1999; accepted 14 December 1999
AbstractÐA vinylogous cephalosporine bearing a dihydroxythiophene moiety as a potential catechol surrogate has been synthe-
sised (I-e-ꢀ). Even if the anti staphylococcus spectrum displayed by this compound is of interest, its activity against Pseudomonas
species, expected for such a structure, remains disappointing. # 2000 Elsevier Science Ltd. All rights reserved.
Catechol containing b-lactams has attracted a lot of
interest during the last 10 years. They penetrate into
Gram negative bacteria via an illicit transport by using
a Ton B dependent iron transport system.1 RU 59863
(I-a-ꢀ),2 a vinylogous catechosporin displays a very
broad spectrum of Gram positive and Gram negative
activity, including Pseudomonas strains which are resis-
tant to various b-lactams including carbapenems.
Hydroxypyridones (b) have successfully been used as
catechol surrogates2,3 (Fig. 1). In the present paper, we
wish to report the synthesis of a vinylogous cephalos-
porin I-e-ꢀ bearing a dihydroxythiophen moiety as
potential isoster of a catechol group. This function has
been designed on the basis of a very strong anti-
pseudomonal activity of the corresponding 3-cyano-4,5-
dihydroxy (I-c-ꢁ) and 2-cyano-3,4-dihydroxybenzene
(I-d-ꢁ) containing cephalosporins.2
Hydroxyl groups were protected using methoxyethoxy-
methyl chloride in the presence of diisopropylethyla-
mine a€ording 5, which could be used without further
puri®cation. Saponi®cation of 5, followed by decarbox-
ylation in re¯uxing ethanol, led to 6. This compound
was in equilibrium between its tautomeric forms (6a and
6b).6 Cleavage of the remaining protection was accom-
plished with TFA in CH2Cl2, leading to 7.
13C and 1H NMR studies performed in methanol, as well
as IR analysis demonstrated that this compound was pre-
sent only in the dihydroxy thiophene tautomeric form 7a.7
Consequently, we undertook the synthesis of I-e, by using
the same synthetic scheme as previously described for the
synthesis of cathecosporines (Scheme 2). The challenge
was the construction of the dihydroxythiophen moiety [I].
Before synthesising the aimed molecule (I-e-ꢀ), we had
checked that 2-cyano-3, 4-dihydroxythiophene predom-
inantly existed in the dihydroxy tautomeric form (7a), as
expected for such compounds.4 This compound was
prepared according to Scheme 1.
Reduction of 5 using tri-ter-butoxyalumino hydride in
THF gave the alcohol 8 without a€ecting either the
cyano function or the thiophene ring. MnO2 oxydation
of 8 provided the aldehyde 9, which was puri®ed by
chromatography.
The intermediate 3 was obtained by reaction of ethyl
thioglycolate 1 with bromoacetonitrile 2 in the presence
of sodium ethoxide in ethanol. After in situ addition of
two additional equivalents of sodium ethylate and di-
ethyl oxalate, the disodium salt of 4 was precipitated by
addition of methylene chloride. This compound was
solubilized in water and 4 was precipitated by sub-
sequent addition of 2N HCl.
As the classical techniques, previously developed in
catechol series, for the synthesis of a-chloroesters start-
ing from aldehydes5 were unsuccessful, we envisaged the
use of a modi®ed version of the approach developed by
Robert et al.8 (Scheme 3). To our knowledge, it has
never been applied on thiophene derivatives.
The ole®nic derivative 10 was obtained by condensation
of malononitrile on 9 with a catalytic amount of piper-
idine, in the presence of molecular sieves. Epoxydation
using a stoichiometric amount of triethylamine and ter-
butylhydroperoxide a€orded the desired epoxyde 11.
*Corresponding author. Fax: +33-1-49-91-50-87; e-mail: christophe.
dini@hmag.com
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(99)00697-6

350
C. Dini, J. Aszodi / Bioorg. Med. Chem. Lett. 10 (2000) 349±352
Figure 1.
Substitution of chlorine with hydroxyphthalimide on 13
under phase transfer catalysis conditions provided 14a
in 50% yield. These conditions limited the formation of
14b.
Deprotection of 14a at
10 ꢀC with hydrazine in
methanol a€orded the unstable hydroxylamine 15,
which had to be reacted in situ with the ketoacid 20 to
give 16 after chromatographic puri®cation. Coupling of
16 with 21 in the presence of EDC provided, after pur-
i®cation, the desired 17 as a syn-oxime in 16% overall
yield from 14a.
Figure 2.
After ®ltration and evaporation of the solvent, 11 was
treated by 1 N HCl in THF (1.3 equivalent) a€ording 12
which was immediately esteri®ed by addition of an
excess of diphenyldiazomethane to provide 13.9
The use of sodium iodide in the presence of iodine led to
the formation of the fragile iodo analogue 18 (mixture E/Z
isomers). The coupling of 18 with quinoline furnished 19
which was then fully deprotected with TFA in the pre-
sence of anisole to provide I-e in a (70:30) E:Z ratio.5
By carrying out the reaction sequence from 9 to 13 with-
out any puri®cation of the intermediates, 13 was obtained
in 64% overall yield, after silica gel chromatography.
Scheme 1. (i) EtONa (1.1 equiv), EtOH; (ii) 1. (CO2Et)2, EtONa (2 equiv), EtOH; 2. HCl 2N; (iii) MEMCl, (iPr)2NEt, CH2Cl2; (iv) KOH, EtOH,
then H+, then EtOH rfx; (v) TFA/CH2Cl2 (1/2) 20 min rt then neutralised.
Scheme 2.

C. Dini, J. Aszodi / Bioorg. Med. Chem. Lett. 10 (2000) 349±352
351
Scheme 3.
Scheme 4. (i) (tBuO)3AlH 6 equiv THF 24 h rt; (ii) MnO2, CH2Cl2, 5 ꢀC; (iii) NCCH2CN, piperidine 0.1 equiv, dioxane, MS 4A, 5 ꢀC 40 min; (iv)
tBuOOH, Et3N, dioxane, 20 min 5±10 ꢀC; (v) 1. HCl 1 N (1.3 equiv), THF, 1 h, rt; 2. Ph2CN2, 2 h, rt; (vi) Et3NBn+ Cl (0.1 equiv), NaHCO3, N-
hydroxyphthalimide, CH2Cl2, H2O, 13 h rt.
Scheme 5. (vii) 1. H2NNH2.H2O, MeOH 10 ꢀC 45 min, 2. 20 , CH2Cl2 rt 2 h; (viii) 21, EDC, CH2Cl2, 45 min rt; (ix) NaI, I2 (cat.), acetone, 1 h rt;
(x) Quinoline, CH2Cl2, 1 h 30 rt; (xi) TFA - anisole (9±1), 1 h rt.
The ®nal product (I-e) was tested in vitro against a
Table 1.a
panel of Gram positive and Gram negative strains,
using I-b, I-c and I-d as comparators (Table 1).
I-b-ꢁ
I-c-ꢁ
I-d-ꢁ
I-e-ꢀ
S. aureus (20 strains)
P. aeruginosa (40 strains)
0.92
3.12
1.40
0.06
3.6
0.12
0.17
38
Contrary to the expectations, this molecule is almost
inactive against Pseudomonas strains. Also, the compound
displays highly potent activity against Staphylococci,
aGeometric mean of MICs (mg/mL).

352
C. Dini, J. Aszodi / Bioorg. Med. Chem. Lett. 10 (2000) 349±352
which is unusual for either a catechol or hydroxy-
pyridone derivative.
OCH2CH2O), 4.02 (m, 2H, OCH2CH2O), 4.59 (s, S±CH2-CˆO),
5.28 (s), 2H, OCH2O), 6.61 (s, <1H, S±CHˆC), 7.91 (sl, ꢁ1H,
1
1
OH). IR (CHCl3): 3550, 3290 cm (OH), 2220 cm (CN),
1578,1492 cm 1 (heterocycle); 6a major tautomer. MS (ES): 229+
(M+H+).
References and Notes
1
7. Data for 7: H NMR (CD3OH): 6.46 (s,=CH-). 13C NMR
1. Guerinot, M.-L. Annu. Rev. Microbiol. 1994, 48, 743.
2. Aszodi, J.; Bonnefoy, A.; Chantot, J.-F.; Dini, C.; Fauveau,
P.; Humbert, D. Abstracts of the 34th Interscience Conference
on Antimicrobial Agents and Chemotherapy 1994, 34, 161.
3. Dobbin, P. S.; Hider, R. C.; Hall, A. D.; Taylor, P. D.;
Sarpong, P.; Porter, J. B.; Xiao, G.; Van der Helm, D. J. Med.
Chem. 1993, 36, 2448.
4. Melvin, Jr., L. S.; Hada, W. A.; Rusek, F. W.; Bordner, J.
Tetrahedron Lett. 1993, 34, 8229.
5. Aszodi, J.; Chantot, J.-F.; D'Ambrieres, S.; Dini, C.; Fau-
veau P.; Humbert D. EP: 94/628562/A1 1994.
6. Data for the tautomeric mixture 6a/6b (95/5): 1H NMR
(CDCl3): 3.43 (s, OCH3) 3.44 (s, OCH3) total 3H, 3.67 (m, 2H,
(CD3OH): 83.4 (CN), 105.7(=CH-); 115.0, 145.2, 156.0 other
1
C. IR (Nujol): 3100±2300 cm (general absorption); 2226
1
1
cm (CN); 1590 cm 1, 1512 cm (heterocycle). MS (EI):
141+ (M+H+).
8. Guinamant, J.-L.; Jaguelin, S.; Robert, A. Tetrahedron
1986, 42, 2275±2281.
9. Data for 13: 1H NMR (CDCl3): 3.31 (s, 3H, OCH3), 3.36 (s,
3H, OCH3), 3.48 (m, 2H, OCH2CH2O), 3.58 (m, 2H, OCH2-
CH2O), 3.82 (m, 2H, OCH2CH2O; MEM), 3.92 (m, 2H,
OCH2CH2O), 5.17 to 5.41 (m, 4H, OCH2O), 5.98 (s, 1H,
ArCHClCO2), 6.91 (s, 1H, C (O)OCHPh2), 7.34 (m, 10H, Ph).
IR (CHCl3): 2221 cm 1 (CN), 1746 cm 1 (CO2R) MS (SIMS):
576+ (M+H+).