Rearrangement of unsym-azetidinone disulphides to 2β-(thio-substituted methyl) penams

Alpegiani, Marco; Giudici, Franco; Perrone, Ettore; Borghi, Daniela

doi:10.1016/s0040-4039(00)97436-7

Cited by 9 publications

(5 citation statements)

References 17 publications

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“…[63][64][65] Interestingly, however, at least one literature example (shown in Scheme 7) indicates that an intramolecular reaction of this type can occur without catalysis and at relatively modest temperatures. 66 In this example, the sulfur leaving group (2-mercaptobenzothiazole anion) is comparable to the hydrodisulfide leaving group (RSS -) in the leinamycin reaction as judged by the pK a values of the conjugate acids. 67,68 Finally, we considered attack of thiolate at the S2position of the 1,2-dithiol-3-one 1-oxide heterocycle.…”

Section: Discussionmentioning

confidence: 82%

“…Alternatively, it is possible that the trisulfide 6 forms and is subsequently converted directly to the episulfonium ion ( 5 ) by intramolecular reaction of the trisulfide moiety with the proximal C6−C7 alkene as shown in Scheme . It is unclear whether such a process can account for the kinetically rapid 14 thiol-triggered activation of leinamycin because, typically, reactions of this sort, involving electrophilic addition of S−S bonds to alkenes, require high temperatures or Lewis acid catalysis. − Interestingly, however, at least one literature example (shown in Scheme ) indicates that an intramolecular reaction of this type can occur without catalysis and at relatively modest temperatures . In this example, the sulfur leaving group (2-mercaptobenzothiazole anion) is comparable to the hydrodisulfide leaving group (RSS - ) in the leinamycin reaction as judged by the p K a values of the conjugate acids. , …”

Section: Discussionmentioning

confidence: 99%

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Activation of Leinamycin by Thiols: A Theoretical Study

Breydo

Gates

2002

J. Org. Chem.

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Reaction of thiols with the 1,2-dithiolan-3-one 1-oxide heterocycle found in leinamycin (1) results in the conversion of this antitumor antibiotic to a DNA-alkylating episulfonium ion (5). While the products formed in this reaction have been rationalized by a mechanism involving initial attack of thiol on the central sulfenyl sulfur (S2') of the 1,2-dithiolan-3-one 1-oxide ring, the carbonyl carbon (C3') and the sulfinyl sulfur (S1') of this heterocycle are also expected to be electrophilic. Therefore, it is important to consider whether nucleophilic attack of thiol at these sites might contribute either to destruction of the antibiotic or conversion to its episulfonium ion form. To address this question, we have used computational methods to examine the attack of methyl thiolate on each of the three electrophilic centers in a simple analogue of the 1,2-dithiolan-3-one 1-oxide heterocycle found in leinamycin. Calculations were performed at the MP2/6-311+G(3df,p)//B3LYP/6-31G level of theory with inclusion of solvent effects. The results indicate that the most reasonable mechanism for thiol-mediated activation of leinamycin involves initial attack of thiolate at the S2'-position of the antibiotic's 1,2-dithiolan-3-one 1-oxide heterocycle, followed by conversion to the 1,2-oxathiolan-5-one intermediate (3).

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Activation of Leinamycin by Thiols: A Theoretical Study

Breydo

Gates

2002

J. Org. Chem.

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“…Starting from the 6,6-dibromopenicillanate sulfoxide tethered to Merrifield resin [6(M)], treatment with 2-MBT under the optimized conditions (1.5 equiv, benzene reflux), gave exclusively the unsymmetrical disulfide 14(M), which then underwent recyclization to 16(M) upon the addition of sulfuryl chloride in dichloromethane at -40°C. 19 After cleavage with AlCl 3 and esterification with diazomethane, the methyl 6,6-dibromo-2b-chloromethylpenicillanate (17) was obtained in an overall isolated yield of 70%…”

Section: Methodsmentioning

confidence: 99%

A Versatile Strategy for the Solid-Phase Synthesis of Penicillin Derivatives: Efficient Preparation of 2β-Methyl Substituted Penams as β-Lactamase Inhibitor Analogues

Boggián¹,

Mata²

2006

Synthesis

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A convenient solid-phase method for the synthesis of 2b-methyl substituted penicillins using commercially available resins is described. Functionalization of Merrifield and Wang resin bound penam derivatives was performed by penicillin sulfoxide rearrangement and the products were released from the supports under mild conditions. The utility of this methodology has been demonstrated by synthesizing a small library of penicillin derivatives in moderate to very good overall isolated yields for the multistep synthetic sequence.Many decades after their discovery, penicillins and related b-lactam compounds remain the most commonly prescribed antimicrobials. 1 However, the rapid evolution of bacterial resistance is a cause of major concern in the infectious disease area. 2 The most common form of bacterial resistance to b-lactam antibiotics is the production of blactamase enzymes, 3 which efficiently hydrolyze the amide bond of the b-lactam ring to give products that are devoid of antibacterial activity. b-Lactamases can be grouped into four classes, based on primary sequence homology: classes A, C and D are serine enzymes, while class B are zinc metalloenzymes. Successful treatment of resistant bacteria can often be effected by the co-administration of an antibiotic and a b-lactamase inhibitor. 4 The problem of increasing bacterial resistance against the standard therapy has stimulated further research into blactam chemistry, which has focused on two major areas: a) the synthesis of compounds stable to b-lactamase, that possess both high potency and a broad spectrum of activity both in vitro and in vivo; b) synthesis of new and more efficient inhibitors of both metallo-and serine-b-lactamases.Current commercial serine-b-lactamase inhibitors are only useful against bacterial strains producing class A blactamases. Among these inhibitors, tazobactam 1 5 (Figure 1), is the most active, 6 and interest in 2b-substituted penam derivatives has been increasing considerably since its discovery. In recent years, some of these derivatives have emerged as a second generation of b-lactamase inhibitors active, not only against class A b-lactamases, but also against class C enzymes. 7During the course of our efforts to develop new therapeutic agents for bacterial diseases, 7b,c,8 we became interested in developing a solid-phase synthetic strategy suitable for the generation of 2b-methyl substituted penicillin libraries that could be used for screening new b-lactamase inhibitor analogues. Though solid-phase organic synthesis (SPOS) has been widely used for the preparation of a large number of structurally diverse small organic molecules for combinatorial libraries, 9 its application to properly functionalized bicyclic b-lactams is still to be fully developed. 10 In this paper, we present the results from an extensive study on the attachment of penicillins to two different polystyrene resins and their subsequent functionalization on these solid supports. 11 This work has led to the development of a convenient method for the synthesis o...

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“…In particular, spiro-4-oxazolidinones, which bear heteroatom-substituted quaternary stereocenters, are useful building blocks to construct medicinally relevant compounds and advanced materials, but have not been studied thoroughly. As outlined in Figure , “Kamiya disulfide” A was found to rearrange to 2β-(benzothiazolylthiomethyl)-penams B upon thermolysis . Spirooxazolidinone C and its analogues exhibit antagonistic activity for orexin receptor, and thus are potentially useful for therapeutic or prophylactic treatment of orexin receptor-associated disorders .…”

mentioning

confidence: 99%

“…As outlined in Figure 1, "Kamiya disulfide" A was found to rearrange to 2β-(benzothiazolylthiomethyl)-penams B upon thermolysis. 2 Spirooxazolidinone C and its analogues exhibit antagonistic activity for orexin receptor, and thus are potentially useful for therapeutic or prophylactic treatment of orexin receptorassociated disorders. 3 1,2,4-Triazole derivative D and its analogues exhibit promising antitumor activities.…”

mentioning

confidence: 99%