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Synthesis, Structure, and Antimalarial Activity of Some Enantiomerically Pure, cis ‐fused cyclopenteno‐1,2,4‐trioxanes
Author(s) -
Jefford Charles W.,
Kohmoto Shigeo,
Jaggi Danielle,
Timári Géza,
Rossier JeanClaude,
Rudaz Manyck,
Barbuzzi Olivier,
Gérard David,
Burger Ulrich,
Kamalaprija Philippe,
Mareda Jiri,
Bernardinelli Gérald,
Manzanares Ignacio,
Canfield Craig J.,
Feck Suzanne L.,
Robinson Brain L.,
Peters Wallace
Publication year - 1995
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.19950780312
Subject(s) - chemistry , trioxane , enantiomer , acetal , stereochemistry , conformational isomerism , molecule , organic chemistry , copolymer , polymer
Two pairs of enantiomerically pure cis ‐fused cyclopenteno‐1,2,4‐trioxanes ( 7 , ent ‐ 7 and 8 , ent ‐ 8 ) are prepared ( Schemes 1–3 ). Their identities are established by dye‐sensitized photo‐oxygenation of ent ‐ 7 and 8 , ent ‐ 8 to the allylichydroperxides, reduction to the corresponding alcohols, and conversion to the (1 S )‐camphanates ( Scheme 4 ), the structures of which are determined by X‐ray analysis. The dynamic properties of ent ‐ 7 are investigated by NMR spectroscopy and PM3 calculations. Evidence for an easily accessible twist‐boat conformation is obtained. The in vitro and in vivo antimalarial activities of 7 , ent ‐ 7,8 , and ent ‐ 8 as well as those of the racemic mixtures are evaluated against Plasmodium falciparum, P. berghei , and P. yoelii . No correlation is observed between configuration and activity. Racemates and pure enantiomers have commensurate activities. The mode of action on the intraerythrocytic parasite is rationalized in terms of close docking by the twist‐boat conformer of the trioxane on the surface of a molecule of heme, single‐electron transfer to the OO σ* orbital, and scission to the acetal radical which then irreversibly isomerizes to a C‐centered radical, the ultimate lethal agent ( Scheme 5 ).