Dispiro-1,2,4-trioxane Analogues of a Prototype Dispiro-1,2,4-trioxolane: Mechanistic Comparators for Artemisinin in the Context of Reaction Pathways with Iron(II)

Authors

Yuanqing Tang, University of Nebraska Medical Center
Yuxiang Dong, University of Nebraska Medical Center
Xiaofang Wang, University of Nebraska Medical Center
Kamaraj Sriraghavan, University of Nebraska Medical Center
James K. Wood, The University of Nebraska at OmahaFollow
Jonathan L. Vennerstrom, University of Nebraska Medical Center

Document Type

Article

Publication Date

5-2005

Publication Title

The Journal of Organic Chemistry

Volume

70

Issue

13

First Page

5103

Last Page

5110

Abstract

Single electron reduction of the 1,2,4-trioxane heterocycle of artemisinin (1) forms primary and secondary carbon-centered radicals. The complex structure of 1 does not lend itself to a satisfactory dissection of the electronic and steric effects that influence the formation and subsequent reaction of these carbon-centered free radicals. To help demarcate these effects, we characterized the reactions of achiral dispiro-1,2,4-trioxolane 4 and dispiro-1,2,4-trioxanes 5−7 with ferrous bromide and 4-oxo-TEMPO. Our results suggest a small preference for attack of Fe(II) on the nonketal peroxide oxygen atom of 1. For 4, but not for 5 and 6, there was a strong preference for attack of Fe(II) on the less hindered peroxide bond oxygen atom. The steric hindrance afforded by a spiroadamantane in a five-membered trioxolane is evidently much greater than that for a corresponding six-membered trioxane. Unlike 1, 5−7 fragment by entropically favored β-scission pathways forming relatively stable α-oxa carbon-centered radicals. These data suggest that formation of either primary or secondary carbon-centered radicals is a necessary but insufficient criterion for antimalarial activity of 1 and synthetic peroxides.

Comments

Copyright © 2005 American Chemical Society

Recommended Citation

Tang, Yuanqing; Dong, Yuxiang; Wang, Xiaofang; Sriraghavan, Kamaraj; Wood, James K.; and Vennerstrom, Jonathan L., "Dispiro-1,2,4-trioxane Analogues of a Prototype Dispiro-1,2,4-trioxolane: Mechanistic Comparators for Artemisinin in the Context of Reaction Pathways with Iron(II)" (2005). Chemistry Faculty Publications. 15.
https://digitalcommons.unomaha.edu/chemfacpub/15