Synthesis of isothiochroman 2,2-dioxide and 1,2-benzooxathiin 2,2- dioxide gyrase B inhibitors

Article abstract of DOI:10.1016/S0040-4039(00)00044-7

The design, synthesis and in vitro biological evaluation of isothiochroman 2,2-dioxide and 1,2-benzooxathiin 2,2-dioxide analogues of coumarin inhibitors of gyrase B are described. Compared to coumarin derivatives, compounds of the 1,2-benzooxathiin 2,2-dioxide series display improved inhibitory potency in negative supercoiling of relaxed DNA gyrase. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00044-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1741–1745
Synthesis of isothiochroman 2,2-dioxide and 1,2-benzooxathiin
2,2-dioxide gyrase B inhibitors
Christophe Peixoto,a Patrick Laurin,a Michel Klich,a Claudine Dupuis-Hamelin,b
Pascale Mauvais,b Patrice Lassaigne,b Alain Bonnefoy b and Branislav Musicki a,∗
aMedicinal Chemistry, Hoechst Marion Roussel, 102 Route de Noisy, 93235 Romainville Cedex, France
bInfectious Disease, Hoechst Marion Roussel, 102 Route de Noisy, 93235 Romainville Cedex, France
Received 1 October 1999; accepted 4 January 2000
Abstract
The design, synthesis and in vitro biological evaluation of isothiochroman 2,2-dioxide and 1,2-benzooxathiin
2,2-dioxide analogues of coumarin inhibitors of gyrase B are described. Compared to coumarin derivatives, com-
pounds of the 1,2-benzooxathiin 2,2-dioxide series display improved inhibitory potency in negative supercoiling
of relaxed DNA gyrase. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: antibiotics; glycosidation; hydrogen bonding; structure–activity.
Over the past several years our efforts have been directed towards the design of effective, orally
bioavailable coumarin antibiotics inhibitors of bacterial DNA gyrase.1 Recently, we have disclosed a
series of coumarin congeners bearing at the coumarin part of the molecule amide isosteres (1),2a,b,e
carboxyl group,2c or basic amino groups.2d As in the complexes of these inhibitors with the 24 kDa
N-terminal fragment of gyrase B protein, one of the key interactions is electrostatic/hydrogen bonding
between the ester and carbonyl oxygens of the coumarin moiety and Arg-136,3 we reasoned that the
replacement of the coumarin carbonyl group with a more polar sulfone functionality would lead to
stronger inhibition of DNA gyrase and improved antibacterial activity. Morever, the polar nature of the
sulfone group would confer better aqueous solubility to the analogues. This led to the design of two
series of DNA gyrase inhibitors wherein the coumarin was replaced with isothiochroman 2,2-dioxide
and 1,2-benzooxathiin 2,2-dioxide derivatives.
∗
Corresponding author. Tel: +33-1-4991-4007; fax: +33-1-4991-5087; e-mail: branislav.musicki@aventis.com (B. Musicki)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00044-7
tetl 16324

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The synthesis of isothiochroman 2,2-dioxide inhibitors of gyrase B is depicted in Scheme 1. 3-
Hydroxy-2-methylbenzoic acid (3) was prepared from 3-nitro-2-methylbenzoic acid (2) according to
the literature.4 The acid 3 was converted to methyl ester by HCl/MeOH at reflux in quantitative yield.
Methylation of the free phenol under standard conditions (Me2SO4/K2CO3 in acetone) provided methyl
ether 4. Reduction of the ester group in 4 with LiAlH4 in ether and subsequent conversion of the resulting
benzyl alcohol with CaCl2/HCl furnished benzyl chloride 5. This was converted with ethyl thioacetate in
the presence of NaH in DMF to S-alkyl derivative 6 which was hydrolysed to free acid. Cyclisation of the
acid to isothiochroman 7 was effected with P2O5 in toluene in the presence of Celite. Oxidation of 7 with
3-chloroperoxybenzoic acid in CH2Cl2 gave the sulfone 8 which was demethylated with a mixture of
HBr-acetic acid to provide the free phenol derivative 9 ready for glycosylation. Attempted glycosylation
of the noviose carbonate 10, prepared from noviose and 1,10-carbonyldiimidazole in dichloroethane at
reflux, with 9 under Mitsunobu’s conditions provided a low yield (10%) of the desired α-anomer 12.
Searching for an alternative method of activation of the anomeric position of noviose carbonate 10,
we prepared the corresponding trichloroacetimidate 11 using trichloroacetonitrile in the presence of
Scheme 1. Reagents and conditions: (a) H2, Pd–C/10%, EtOH, rt, 98%; (b) NaNO2, aq. H2SO4, 0°C then reflux, 99%;
(c) MeOH, HCl gas, reflux, quant.; (d) Me2SO4, K2CO3, acetone, rt, 72%; (e) LiAlH4, Et2O, rt, quant.; (f) CaCl2, HCl,
94%; (g) HSCH2CO2Et, NaH, DMF, rt, 72%; (h) NaOH, MeOH, H2O, rt, 86%; (i) P2O5, Celite, toluene, 90°C, 77%; (j)
3-ClC6H4CO3H, CH2Cl2, 0°C, 60%; (k) HBr, AcOH, reflux, 90%; (l) 1,10-carbonyldiimidazole, ClCH2CH2Cl, reflux, 70%;
(m) NC–CCl3, CH2Cl2, Cs2CO3 cat, rt, quant.; (n) BF3–Et2O, CH2Cl2, 84%; (o) ClCO2Et, DMAP, CH2Cl2, rt, 60%; (p)
HC^CCH2ONH2−HCl, LiClO4, Py, rt, 33%

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Scheme 2. Reagents and conditions: (a) DMF, POCl3, ClCH2CH2Cl, rt, 73%; (b) MnO2, KCN, AcOH, MeOH, rt, 68%; (c)
DHP, cat TsOH, Et2O, rt, 71%; (d) MsCl, Et3N, Et2O, rt, 90%; (e) NaH, DMF, 0°C, 82%; (f) 1 M HCl in MeOH, rt, 86%; (g)
11, BF3Et2O, CH2Cl2, 50%; (h) 3-ClC6H4–NCO, DMAP, CH2Cl2, rt, 23%; (i) HC^CCH2ONH2-HCl, LiClO4, Py, rt, 64%; (j)
PPh3, EtO2CN_NCO2Et, CH2Cl2, rt, 15%; (k) Ac2O, DMAP, CH2Cl2, rt; (l) KOMe, MeOH, 0°C, 37% (from 27)
catalytic quantities of Cs2CO3 in CH2Cl2. The imidate 11 underwent smoothly glycosylation with 9
in the presence of BF3–Et2O in dichloromethane to afford 84% of desired α-glycoside 12. As in the case
of coumarin series2a isothiochroman 2,2-dioxide derivative 12 underwent C-acylation at C-3 with ethyl
chloroformate in the presence of DMAP to provide 13. Opening of the noviosyl carbonate part of 13 with
O-propargylhydroxylamine in the presence of LiClO4 in pyridine afforded a thermodynamic mixture of
30- and 20-N-propargyloxycarbamates 14 and 15 (4:1)5 in 33% yield.
The synthetic approach to 1,2-benzooxathiin 2,2-dioxide inhibitors of gyrase B is summarised
in Scheme 2. Vilsmeyer formylation6 of 2-methylresorcinol 17 provided 2,4-dihydroxy-3-
methylbenzaldehyde that was oxidised to the corresponding methyl ester 18 using Corey’s procedure.7
Regioselective tetrahydropyranylation of 18 afforded THP monoprotected derivative 19 in 74% yield.
The phenol 19 was then converted under standard conditions into methanesulfonate 20 that was
subjected to basic cyclisation with NaH in DMF to furnish 1,2-benzooxathiin 2,2-dioxide derivative
21. Deprotection of THP in 21 with HCl/MeOH provided the intermediate 22 ready for glycosylation.
Coupling of 22 with activated noviose carbonate 11 under BF3–Et2O catalysed conditions afforded
α-glycoside 23 in 50% yield after chromatographic separation. Acylation at C-3 of 1,2-benzooxathiin
2,2-dioxide portion of 23 with 3-chlorophenylisocyanate in the presence of DMAP furnished the
corresponding anilide 24. This was subjected to lithium perchlorate catalysed opening of the noviosyl
carbonate portion with O-propargylhydroxylamine in pyridine to provide, similarly to the isothiochroman
2,2-dioxide case, a mixture of regioisomeric 30- and 20-N-propargyloxycarbamates 25 and 26 in the
ratio 4:1, respectively. The 1,2-benzooxathiin 2,2-dioxide analogue 29 bearing 30-(5-methylpyrro-2-
yl)ester at noviose was synthesised by Mitsunobu’s coupling between pyrrole-noviose 272a and 22.
The introduction of an acetyl group at the 3-position of the 1,2-benzooxathiin 2,2-dioxide 28 by the
established technique2a was accompanied by acetylation of 20-OH of noviose. Hydrolysis of this
20-acetate in MeOH with KOMe gave 1,2-benzooxathiin 2,2-dioxide analogue 29.
The results of the inhibition of the supercoiling activity of S. aureus or E. coli DNA gyrase by

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novobiocin, clorobiocin and isothiochroman 2,2-dioxide and 1,2-benzooxathiin 2,2-dioxide derivatives
are shown in Table 1. Also in Table 1 are the corresponding results of the reference compounds
incorporating the coumarin scaffold: 162b (Scheme 1) and 302a (Scheme 2). As predicted, substitution
of the C_O carbonyl group of coumarin 30 by SO2 29 did result in a twofold increase of inhibitory
potency in negative supercoiling of DNA gyrase. However, replacement of -O-CO- of coumarin moiety
16 by -CH2-SO2- in isothiochroman 2,2-dioxide 14 lowered the inhibitory activity by an order of
magnitude. Taking into account the distances between the guanidinium group of Arg-136 and the ester
oxygen and carbonyl group of coumarin ring as 3.2 and 2.6 Å, respectively,3c the principal hydrogen
bonding interaction could be attributed to Arg-136 and the C_O of the coumarin moiety. Decrease
in activity of isothiochroman 2,2-dioxide derivative 14 with respect to 16 could be explained by the
CH2 of 14 hindering the tight binding of the 8-Me group of coumarin to a hydrophobic pocket.
Although the 1,2-benzooxathiin 2,2-dioxide series displayed increased in vitro inhibitory activity when
compared to coumarin analogues, the series was completely devoid of antibacterial activity (MIC >40).
Increased polarity caused by replacement of the coumarin carbonyl group by SO28 completely abolished
the intracellular uptake of the analogues. These results clearly demonstrate that the fine tuning of
lipophylicity of gyrase B inhibitors is essential for their biological activity.
Table 1
In vitro activity of isothiochroman 2,2-dioxide and 1,2-benzooxathiin 2,2-dioxide inhibitors against S.
aureus or E. coli DNA gyrase supercoiling (IC50),a,b and selected in vitro antibacterial activity (MIC)c
In conclusion, we succeeded in replacing the coumarin scaffold by a 1,2-benzooxathiin 2,2-dioxide
skeleton to give analogues that proved to be more potent in inhibiting negative supercoiling of DNA
gyrase. At the same time, however, the highly polar nature of this class of analogues had negative effects
on intracellular permeability and antibacterial activity.
Acknowledgements
We are grateful to the Analytical Department (HMR, Romainville) for performing spectral analysis.

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