3,3,6,6-Tetramethyl-1,2,4,5-tetroxane conformations

Trioxane 210 has been used as a model system by Gu and coworkers to study the antimalarial drug artemisinin 211 (Scheme 137) [97CPL234, 99JST103]. It is the boat/twist form rather than the chair conformer of 210 that describes the subunit in 211. Moreover, geometric parameters and vibrational frequencies can only reliably be computed at the DFT level and by post-Hartree-Fock methods. B3-LYP/6-31G calculations on the conformers of 3,3,6,6-tetramethyl-1,2,4,5-tetroxane show that the chair conformer is stabilized with respect to the twisted conformer by about -2.8 kcal/mol [00JST85]. No corresponding boat conformer was found. 

X-ray studies have shown that 3,3,6,6-tetramethyl-l,2,4,5-tetrathiane exists in the twist conformation 164 in the solid state. According to ab initio calculations at the HF/6-31G, MP2/6-31G, and B3LYP/6-31G levels the twist conformation 164 is 4 kj mol-1 more stable than the chair conformation 165 and the calculated strain energy for twist-to-chair conversion is 61.1 kj mol-1 (Scheme 9). The chair conformation of the parent 1,2,4,5-tetrathiane was calculated to be 10.7 kj mol-1 more stable than the twist form <2004PS2015>. X-ray crystallography has confirmed that in the solid state 3,3,6,6-tetramethyl-l,2,4,5-tetroxane adopts a chair conformation 166 . 

---