Synthesis of 1,2,4-trioxepanes via application of thiol-olefin co-oxygenation methodology.
Thiol-olefin co-oxygenation (TOCO) of substituted allylic alcohols generates beta-hydroxy peroxides that can be condensed in situ with various ketones, to afford a series of functionalised 1,2,4-trioxepanes in good yields. Manipulation of the phenylsulfenyl group in 8a-8c allows for convenient modification to the spiro-trioxepane substituents. Surprisingly, and in contrast to the 1,2,4-trioxanes examined, 1,2,4-trioxepanes are inactive as antimalarials up to 1000 nM and we rationalize this observation based on the inherent stability of these systems to ferrous mediated degradation. FMO calculations clearly show that the sigma* orbital of the peroxide moiety of 1,2,4-trioxane derivatives 4a and 14b are lower in energy and more accessible to attack by Fe(II) compared to their trioxepane analogues 8b and 9b.
Amewu
Richard
R
Department of Chemistry, University of Liverpool, PO Box 147, Liverpool L69 3BX, UK.
Stachulski
Andrew V
AV
Berry
Neil G
NG
Ward
Stephen A
SA
Davies
Jill
J
Labat
Gael
G
Rossignol
Jean-Francois
JF
O'Neill
Paul M
PM
D000475:Alkenes / Q000737:chemistry*; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007501:Iron / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D010082:Oxepins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010100:Oxygen / Q000737:chemistry*; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry*
D000475:Alkenes; D000962:Antimalarials; D010082:Oxepins; D013438:Sulfhydryl Compounds; D007501:Iron; D010100:Oxygen