An Asymmetric Synthesis of 1,2,4-Trioxane Anticancer Agents via Desymmetrization of Peroxyquinols through a Brønsted Acid Catalysis Cascade

Abstract

The desymmetrization of p-peroxyquinols using a Brønsted acid catalyzed acetalization/oxa-Michael cascade was achieved in high yields and selectivities for a variety of aliphatic and aryl aldehydes. Mechanistic studies suggest that the reaction proceeds through a dynamic kinetic resolution of the peroxy hemiacetal intermediate. The resulting 1,2,4-trioxane products were derivatized and show potent cancer cytotoxicity.

Cytotoxicity of Endoperoxides from the Caribbean Sponge Plakortis halichondrioides towards Sensitive and Multidrug-Resistant Leukemia Cells: Acids vs. Esters Activity Evaluation

“…It can be speculated that not only artemisinin-type drugs, but also other endoperoxides may reveal anticancer activity. This hypothesis is substantiated by reports on the cytotoxicity of natural and synthetic endoperoxides towards tumor cell lines [16,17,18,19,20,21,22,23,24,25]. Endoperoxides are, therefore, worth investigating to unravel their full potential as anticancer drug leads.…”

“…There are some discrepancies within the literature concerning the nomenclature of plakortides and their esters: According to reference [22] plakortide I is the acid of the methyl ester plakortide H. Also reference [27] and the reference [32] term the methyl ester plakortide H. In contrast, the reference [38] describes plakortide H as the respective acid and plakortide I as its 11,12-dihydro derivative. In the present manuscript, we refer to plakortide H as the methyl ester, and accordingly compound 1 is the 6-epimer of plakortide H acid, and compound 7 the 6-epimer of plakortide H. There are also discrepancies concerning the structure of plakortic acid: According to reference [20] the natural compound named plakortic acid is rather an epoxide than an endoperoxide. Reference [38] in contrast assigns the structure of the acid of plakortin to plakortic acid.…”

Enantio‐ and Diastereoselective Synthesis of exo‐Peroxyacetals: An Organocatalyzed Peroxyhemiacetalization/oxa‐Michael Addition Cascade

“…[1][2][3][4][5] However,t odate, the corresponding catalytic enantioselective strategies for the synthesis of chiral peroxides are less explored. [6][7][8][9] Moreover,asper our knowledge,there is still ascarcity of methods for the catalytic enantio-and diastereoselective synthesis of peroxides.…”

Asymmetric transformations of achiral 2,5-cyclohexadienones

“…46 Trioxane products 151a and 151b were obtained with high enantioenrichment by using spirobiindane phosphoric acid catalyst 152 . In all cases, the products were formed as a single diastereomer.…”