Studies on chemo- and diastereo-selectivity of the Diels–Alder reactions of sulfinyltoluquinones with cyclopentadiene

Sousa, Andrea Leal de; Filho, José Eduardo Pandini Cardoso; Wladislaw, Blanka; Marzorati, Liliana; Vitta, Cláudio Di

doi:10.1139/v09-070

Search citation statements

Order By: Relevance

Paper Sections

Select...

Citation Types

Supporting

Mentioning

Contrasting

Year Published

2014

2024

Publication Types

Select...

Book1

Article1

Relationship

Self Cite0

Independent2

Authors

Journals

Cited by 2 publications

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

7.15 Synthesis of para- and ortho-Quinones

Weaver¹,

Pettus²

2014

Comprehensive Organic Synthesis II

View full text Add to dashboard Cite

7.15 Synthesis of para- and ortho-Quinones

Weaver¹,

Pettus²

2014

Comprehensive Organic Synthesis II

View full text Add to dashboard Cite

Regioselective Synthesis of Potential Non-Quinonoid Prodrugs of Plasmodione: Antiparasitic Properties Against Two Hemoglobin-Feeding Parasites and Drug Metabolism Studies

Cesar-Rodo,

Dupouy,

Häberli

et al. 2024

Molecules

View full text Add to dashboard Cite

Ψ-1,4-naphthoquinones (Ψ-NQ) are non-quinoid compounds in which aromaticity—found in 1,4-naphthoquinones—is broken by the introduction of an angular methyl at C-4a or -8a. This series was designed to act as prodrugs of 1,4-naphthoquinones in an oxidative environment. Furthermore, from a medicinal chemistry point of view, the loss of planarity of the scaffold might lead to an improved solubility and circumvent the bad reputation of quinones in the pharmaceutical industry. In this work, we illustrated the concept by the synthesis of Ψ -plasmodione regioisomers as prodrugs of the antimalarial plasmodione. The presence of a chiral center introduces a new degree of freedom to be controlled by enantioselectivity and regioselectivity of the cycloaddition in the Diels–Alder reaction. The first strategy that was followed was based on the use of a chiral enantiopure sulfoxide to govern the stereoselective formation of (+)Ψ-NQ or (−)Ψ-NQ, depending on the chirality of the sulfoxide (R or S). New sulfinylquinones were synthesized but were found to be ineffective in undergoing cycloaddition with different dienes under a wide range of conditions (thermal, Lewis acid). The second strategy was based on the use of boronic acid-substituted benzoquinones as auxiliaries to control the regioselectivity. Using this methodology to prepare the (±)Ψ-NQ racemates, promising results (very fast cycloaddition time: ~2 h) were obtained with boronic acid-based quinones 25 and 27 in the presence of 1-methoxy-1,3-butadiene, to generate the 4a- and the 8a-Ψ-plasmodione regioisomers 1 and 2 (synthesized in six steps with a total yield of 10.5% and 4.1%, respectively. As the expected prodrug effect can only be revealed if the molecule undergoes an oxidation of the angular methyl, e.g., in blood-feeding parasites that digest hemoglobin from the host, the antimalarial and the antischistosomal properties of both (±)Ψ-NQ regioisomers were determined in drug assays with Plasmodium falciparum and Schistosoma mansoni. Metabolic studies under quasi-physiological conditions and LC-MS analyses were undertaken to reveal the generation of plasmodione from both the 4a- and the 8a-Ψ-plasmodione regioisomers.

show abstract

Studies on chemo- and diastereo-selectivity of the Diels–Alder reactions of sulfinyltoluquinones with cyclopentadiene

Cited by 2 publications

References 55 publications

7.15 Synthesis of para- and ortho-Quinones

7.15 Synthesis of para- and ortho-Quinones

Regioselective Synthesis of Potential Non-Quinonoid Prodrugs of Plasmodione: Antiparasitic Properties Against Two Hemoglobin-Feeding Parasites and Drug Metabolism Studies

Contact Info

Product

Resources

About