Cyclic sulfonamides

Acylation of a usually non-nucleophilic cyclic sulfonamide 52 has also been achieved under by deprotonation of the N-H by butyllithium followed by addition of various unsaturated acid chlorides (Equation 10) <2005TA761>. 

Clerici et al. in their extensive work on cyclic sulfonamides have demonstrated that the compounds 69 and 70 undergo base-induced ring cleavage via elimination of diethylcyanamide and SO2 to afford 71 (Equation 14) <2001TL5455>. Various mechanisms are feasible, however, the necessity for base in the reaction medium implies deprotonation, either at nitrogen or carbon, followed by fragmentation as outlined below (Scheme 7). 

The cyclic sulfonamide (377) can be prepared by heating 5-aminopentanesulfonyl chloride. 4-Chloro-2-benzoylbenzenesulfonyl chloride reacts with acetamidine to give the o-benzoyl-N-phenylsulfonylamidine which can be cyclized with base to give the fully unsaturated 1,2-benzothiazepine 1,1-dioxide (378 R = R1 = H). Alkyl-substituted amidines give the 3-imino derivatives (66USP3377357). 

The cyclic sulfonamide (141) can be prepared by heating 5-aminopentanesulfonyl chloride. The ketone HC = CC(0)CH = CHSCN reacts with amines to give the l,2-thiazepin-5-one system (e.g. 142) (61CB1606). 

The ring-closing metathesis reaction has also been applied to the formation of a seven-membered cyclic sulfonamide C1999TL4761 >. Thus, heating 27 at reflux in dichloromethane (DCM) with ruthenium catalysis (Grubbs I catalyst) gave 28 in high yield (Equation 5). 

The reactivity of cyclic sulfonamidates and sulfinimidates was discussed in CHEC-II <1996CHEC-II(4)409>. Nucleophilic substitution in both rings leads to cycle opening, and these compounds are found to be excellent precursors for the synthesis of important biological active compounds, for example, a-amino acids. 

Substituted o-benzenesulfonamide 61 was found to be a good source for the synthesis of 4-methoxybenzyl esters by the reaction with alcohols and phenols in the presence of sodium hydride at room temperature <1998TL1799>. Treatment of cyclic sulfonamide 61 with aqueous KOH in dimethylformamide (DMF) yielded 4-methoxybenzyl alcohol together with benzenesulfonamide 53 (Scheme 5). 

As a weak base (pKa = 3.9), pantoprazole is highly ionized at low pH and readily accumulates in the highly acidic canalicular lumen of the stimulated parietal cell. In this acidic environment, pantoprazole is rapidly converted to the active species, a cationic cyclic sulfonamide, which binds covalently to cysteine residues on the luminal (acidic) surface of H+, K+-ATPase to form a mixed disulphide, thereby causing irreversible inhibition of gastric proton pump function. As H+, K+-ATPase represents the final step in the secretary process, inhibition of this enzyme suppresses gastric acid secretion regardless of the primary stimulus [1],... 

Intramolecular aziridinations of the olefinic sulfonamides 297, by means of the iminoiodane derivatives 298, have recently been demonstrated (Scheme 85) (OOOL2327). Ring-opening reactions of the bi- and tricyclic sultams 299, thus obtained, with selected nucleophiles were explored and provide access to functionalized cyclic sulfonamides. 

Camphor-10-sulfonic acid (1) is available in large quantities in both enantiomeric forms. In only 3 steps the cyclic sulfonamide 2 (sultam) can be synthesized, which can be acylated with acid chlorides after deprotonation with sodium hydride (Scheme 1) [1, 2]. The resulting amides 3 are considerable more reactive towards nucleophiles than the corresponding carboxylic esters and the a,/ -unsaturated derivatives undergo, with excellent selectivities, Diels-Alder reactions or Michael additions under mild conditions. Al-... 

In 1998, Langlois et al. completed the third synthesis of manzamine C using a strategy based on Sila-Cope elimination (Scheme 8.9) [80]. In this approach, the key intermediate, piperidine derivative 146, was prepared in six steps from 2-methylpyr-idine 143. Oxidation of 146 afforded a mixture of diastereomeric N-oxides 147 and 148. Sila-Cope elimination of N-oxide 147 led to compound 149, while Cope elimination of N-oxide 148 led to compound 150. Oxidative cleavage of the N-O bond in 149 followed by treatment with N-chlorosucdnimide provided the chlor-oamine 153. Elimination, hydrolysis, ditosylation, and finally basic treatment of the ditosylate intermediate afforded the cyclic sulfonamide 124, which is the direct synthetic precursor of manzamine C [73]. 

The intermolecular addition of carbamates to 1,3-dienes (equation 147) under mild conditions has been described as well. The hydrothiolation of 1,3-dienes has also been reported. " Other related conjugate additions can be performed over methylenecyclopropanes (equation 148) with sulfonamides and the resulting product cyclizes by a second hydroamination of an olefin, finally yielding cyclic sulfonamides. This behavior is reproduced in a similar reaction for the ring opening of vinylcyclopropanes with sulfonamides. One more example in this group of reactions is the synthesis of dUiydrobenzofurans from aryl-allyl ethers. ... 

Ueda et al. reported a tandem radical addition-cycUzation reaction in aqueous media [184]. This reaction was initiated by single-electron transfer from indium to an alkyl iodide. Fragmentation of the iso-propyl iodide radical anion generated the iso-propyl radical, which triggered the addition/cyclization tandem. Final SET and in situ hydrolysis delivered cyclic sulfonamides in good yield but low stereoselectivity. 

A furtlier reported example is the preparation of cyclic sulfonamides (Scheme 50) [132, 133[. The Boc group was removed from the diene attached to the solid support via a flexible linker (111), and this was followed by an alkylation to create diversity. Entity 112 was then subjected to RCM using Grubbs catalyst 101 to yield the desired cyclic sulfonamides 113 in good to excellent yields without the need for an alkene co-factor. 

Glutamylcysteine synthetase, cysteine, or methionine was 100 times more reactive to hypochlorous acid in comparison with amino acids that did not contain thiol groups (Folkes et al., 1995). Sublethal exposures to HOCl decreased GSH levels in several cell types (Vissers and Winterboum, 1995 Pullar et al., 1999). In a study by Pullar et al. (1999) using human umbilical vein endothelial cells, doses of 25 nmol of HOCl and less were sublethal when the exposure was done over 10 min, there was a concentration-dependent loss of intracellular GSH. Tissue exposure to HOCl resulted in a reduction of GSH. The metabolite of the HOCl interaction with GSH was an unexpected cyclic sulfonamide that was exported from the cell. The expected metabolites of glutathione disulfide (GSSH) and GSH sulfonic acid were actually minimal (Pullar et al., 2001). Inactivation of acetylcholinesterase by HOCl could be a contributory cause of airway hyperreactivity (den Hartog et al., 2002). 

Recently developed powerful methodologies for the generation of these cyclic sulfonamides include pericyclic reactions as the intramolecular Diels-Alder reaction affording bi- or polycyclic sultams Method K) (Scheme 48). 

Cyclic sulfonamides were prepared 20 to 25 years ago (Ciaperoni et al., 1965 Kndllmuller, 1970, 1971a, 1971b). These authors reacted 1,6-hexane-diamine and 1,10-decanediamine with sulfamide to form the macrocyclic sulf-amides. Arya and Shenoy (1976) reported that when the methylene chain between the diamines was less than eight carbon atoms, a 1 1 cyclization took place. A 2 2 cyclization took place when the methylene chain was longer than eight carbon atoms (method Z-18). These authors also reported a 2 2 cycli-... 

Reductive cleavage. Certain cyclic sulfonamides suffer double cleavage of C—S and N—S bonds, but an A -benzyl group is more labile. 

A poly(cyclic sulfonamide) was obtained by Goethals and his group80 in a radical-initiated cyclo-polymerization of a 1,6-diene ... 

Cyclic sulfonamides are Lermed sultams. From the enantiomeric 10-camphorsulfonic acids, both enantiomers of camphorsultam (49) are readily available by reduction of the intermediate sulfon-imide 484fi 50 and are commercially available. They have been used for the formation of amides with unsaturated acids, which are useful chiral dienophiles and dipolarophiles (Sections D. 1.6,1.1.1- and D. 1.6.1.2.1.) or undergo osmium tetroxide catalyzed dihydroxylations (Section D.4.4.). Other amides may be used for enolate reactions (Sections D.1.1.1.3.1., D.l.5.2.1. and D.4.3.). The. V-fluorinated derivative was obtained by direct fluorination of the sultam with 10% fluorine in nitrogen at low temperature5 , and has been used for the enantioselective formation of C —F bonds (Section D.3.). 

For several years Hallberg has used MW-promoted reactions for optimization of different types of aspartyl protease inhibitors [7]. The Suzuki-Miyaura coupling was recently used to introduce biaryl moieties in cyclic sulfonamide HIV-1 protease inhibitors. A series of sixteen reactions were performed with fair to moderate yields and the reaction times were, in all examples except two, limited to only 5 min... 

Scheme 15.31. Synthesis of a cyclic sulfonamide HIV-1 protease inhibitor.

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