Synthesis of chiral spiropyrazoline-β-lactams and spirocyclopropyl-β-lactams from 6-alkylidenepenicillanates

Santos, Bruna S.; Gomes, Clara S. B.; Melo, Teresa M. V. D. Pinho e

doi:10.1016/j.tet.2014.03.109

Cited by 20 publications

(11 citation statements)

References 36 publications

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“…Initially, in vitro cytotoxicity assays in TZM-bl cells were performed for a wide range of γ-lactams, and some β-lactams previously synthesized ( Figure 2) [23]. From a library of 19 compounds, 18 of them showed no cytotoxicity and their antiviral activity was evaluated ( Table 2).…”

Section: Anti-hiv Activitymentioning

confidence: 99%

“…Spiro-2-pyrazoline--lactams were obtained from the reaction with acrylonitrile, acrylates or methyl vinyl ketone, whereas the reaction with N-substituted-maleimides afforded spiro-1-pyrazoline--lactams. Those studies led to the discovery of a lead compound with remarkable anti-HIV (human immunodeficiency virus) and antiplasmodial properties [22][23][24][25].…”

Section: Introductionmentioning

confidence: 99%

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Spiro-Lactams as Novel Antimicrobial Agents

Alves

Caratão

et al. 2020

CTMC

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Introduction: Structural modulation of previously identified lead spiro-β-lactams with antimicrobial activity was carried out. Objective: The main objective of this work was to synthesize and evaluate the biological activity of novel spiro-lactams based on previously identified lead compounds with antimicrobial activity. Methods: The target chiral spiro-γ-lactams were synthesized through 1,3-dipolar cycloaddition reaction of a diazo-γ-lactam with electron-deficient dipolarophiles. In vitro activity against HIV and Plasmodium of a wide range of spiro-β-lactams and spiro-γ-lactams was evaluated. Among these compounds, one derivative with good anti-HIV activity and two with promising antiplasmodial activity (IC50 < 3.5 µM) were identified. Results: A novel synthetic route to chiral spiro-γ-lactams has been established. The studied β- and γ- lactams were not cytotoxic, and three compounds with promising antimicrobial activity were identified, whose structural modulation may lead to new and more potent drugs. Conclusion: The designed structural modulation of biologically active spiro-β-lactams involved the replacement of the four-membered β-lactam ring by a five-membered γ-lactam ring. Although conformational and superimposition computational studies revealed no significant differences between β- and γ- lactam pharmacophoric features, the studied structural modulation did not lead to compounds with a similar biological profile. The observed results suggest that the β-lactamic core is a requirement for the activity against both HIV and Plasmodium.

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Section: Anti-hiv Activitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Spiro-Lactams as Novel Antimicrobial Agents

Alves

Caratão

et al. 2020

CTMC

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“…In analogy, chiral spiropyrazolinepenicillanates 101, 102 and 103 were obtained in a stereoselective fashion via 1,3-dipolar cycloaddition of 6-alkylidenepenicillanates 100, prepared through Wittig reaction of the appropriate benzhydryl 6-oxopenicillanate 98 and phosphorus ylides 99, with the corresponding diphenyldiazomethane, diazomethane and phenyldiazomethane (Scheme 30). 75…”

Section: Scheme 29mentioning

confidence: 99%

An update on the synthesis and reactivity of spiro-fused β-lactams

Thi¹,

D’hooghe²

2019

Arkivoc

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β-Lactam ring-containing compounds play a pivotal role in drug design and synthetic chemistry. Spirocyclic βlactams, representing an important β-lactam subclass, have recently attracted considerable interest with respect to new synthetic methodologies and pharmacological applications. The aim of this manuscript is to review the recent progress made in this field, covering publications disseminated between 2011 to 2018 concerning the synthesis and application of spirocyclic β-lactams. In the first part, new approaches to the synthesis of spirocyclic β-lactams, including Staudinger synthesis, cyclization and transformation reactions, will be presented. The reactivity and biological properties of spiro-β-lactams will be described in the second and third part, respectively.

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“…As an extension of the work of Sheehan [38a] and Habich, [38b] Pinho e Melo et al further explored their 1,3‐dipolar cycloaddition reactions with diazomethane, phenyldiazomethane and diphenyldiazomethane to obtain chiral spiropyrazoline penicillanates stereoselectively [38c] . Also, D'hooghe et al carried out synthetic exploration of 3‐methylene‐4‐(trifluoromethyl)azetidin‐2‐ones [generated from 3‐oxo‐4‐trifluoromethyl‐β‐lactams] to synthesize spirocyclic azetidin‐2‐one isoxazolidine systems via 1,3‐dipolar nitrone‐olefin cycloaddition reaction with α‐phenylnitrones (Scheme 1, Eq.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of α‐Heterocycle Anchored Spirocyclic Azetidin‐2‐ones in a Minute by p‐TSA Catalyzed Cyclocondensation of Azetidin‐2,3‐diones with Difunctionalized Substrates

et al. 2021

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Monocyclic azetidin‐2,3‐diones provide easy extensions to spiro‐fused azetidin‐2‐ones upon p‐toluenesulfonic acid (p‐TSA) catalyzed cyclocondensation reaction with difunctionalized substrates [mercaptoacids (mercaptoacetic acid, 2‐mercaptopropionic acid, 3‐mercaptopropionic acid), ethan‐1,2‐dithiol, ortho‐difunctionalized benzenes (ortho‐phenylenediamine, ortho‐aminothiophenol)]. 1,3‐Oxathiolan‐5‐one/6‐one, 1,3‐dithiolane, 2,3‐dihydrobenzo[d]imidazole and 2,3‐dihydrobenzo[d]thiazole tethered spirocyclic azetidin‐2‐ones were obtained in good overall isolated yields (69–89 %) in a very short‐time duration (max 1 min) using toluene Dean‐Stark reflux/dichloromethane rt stirring conditions. The stereochemical and spectral studies, stabilities and diastereoisomeric ratio for trans and cis spiro‐fused products are reported. The trans and cis configuration has been assigned to spiro‐β‐lactams wrt the stereochemical relationship between sulfur atom (at spiro centre) and the vicinal methine hydrogen atom at C3/C2. The absolute configuration of one trans 1,3‐oxathiolan‐5‐one fused spirocyclic azetidin‐2‐one was clearly identified by X‐ray single crystal structure analysis.

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Synthesis of chiral spiropyrazoline-β-lactams and spirocyclopropyl-β-lactams from 6-alkylidenepenicillanates

Cited by 20 publications

References 36 publications

Spiro-Lactams as Novel Antimicrobial Agents

Spiro-Lactams as Novel Antimicrobial Agents

An update on the synthesis and reactivity of spiro-fused β-lactams

Synthesis of α‐Heterocycle Anchored Spirocyclic Azetidin‐2‐ones in a Minute by p‐TSA Catalyzed Cyclocondensation of Azetidin‐2,3‐diones with Difunctionalized Substrates

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