1.2.4- Trioxane, 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. 

Also for 1,2,4-trioxane, from MM3 calculations, a structure close to a chair with the protons and substituents in axial and equatorial positions, respectively, was suggested [92JCS(CC)1689]. The substituted derivatives 63 (Scheme 25) have substituents R [Me, iPr, CH2HgBr, CH(HgBr)Me] in an equatorial position (all in agreement with standard conformational principles), and only in 64-66 were axial methyl substituents reported, based on NOE measurements and 7c-h coupling constants [92JCS(CC)1689]. 

The S-trioxane radical cation was investigated in freon matrix and the changes of ESR spectra with temperature, arising from conformational interconversion of the ring were observed23. 

Saturated heterocyclic rings containing oxygen, nitrogen, or sulfur atoms also exist preferentially in stable, chair conformations resembling that of cyclohexane. Physical measurements, such as those of electron diffraction and dipole moments, have shown this conformation for p-dioxane, -s-trioxane, ° paraldehyde, s-trithiane, and 2,4,6-trimethyl-s-tri-... 

Muller and coworkers have recently reported the molecular behavior of 1,3,5-trioxane in a cyclophosphazene inclusion compound using H-2 NMR [68]. The experimental data were obtained by variable-temperature line shape analysis, spin-spin and spin-lattice relaxation time measurements and by 2D exchange between 30 and 370 K. At room temperature, highly mobile trioxane guests were observed. They undergo various overall and conformational motions which give rise to substantial orientational disorder within the hexagonal cyclophosphazene channels. 

Anisotropy of C—O bond deduced from paraldehyde and trioxan then used to specify non-planar conformations of 1,4-dioxan and the other molecules named... 

Semi-empirical and ab initio calculations have been performed on 5-hydroxymethyl-3,5,6,6-tetra-methyl-l,2,4-trioxane(14) <911 JQ23l>. A comparison ofthe AMI, PM3,3-21G, and 6-3IG optimized geometries, all of which are chair conformations, are in excellent agreement with the x-ray structure. Similar comparisons have been made for artemisinin (9) <94IJQ11 >. Agreement between the ab initio... 

IG and 6-3IG calculations is excellent both give 0(1)—0(2) bond lengths close to the value determined by x-ray. The trioxane ring assumes a twist-boat conformation and the 01—02 bond length calculated by 3-2 IG (1.462 A) lies close to the experimental value (1.478 A). This result shows... 

Crystallographic evidence amply demonstrates that the trioxane ring is similar in shape and conformational preference to cyclohexane. The barrier for chair-to-chair interconversion, a hitherto unknown quantity, has been determined by a dynamic NMR spectral study <93JCS(P1)1927). The behavior of 3,3,5,5,6,6-hexamethyl-1,2,4-trioxane (27) is typical. Despite the high degree of substitution, MM3 calculations show that it exists as a chair in the ground state. The value determined... 

Trioxanes. 1,2,4-Trioxanes (2) can be prepared by reaction of hemiperoxy-acetals (1) with Hg(OAc)3 (1 cquiv.) catalyzed by HC104. This route can show high diastcrcoselectivity. Thus the trioxanc 3 has the chair conformation with all three... 

Artemisinin 17, 1,2,4-trioxane 18 itself, and some ring-fused, artemisinin-analogous 1,2,4-trioxanes have been studied theoretically and reported previously in CHEC-II(1996). While the nonsubstituted 1,2,4-trioxane ring prefers an envelope conformation, stmcturally related analogs favor a twist boat conformation. l,2,4-Trioxane-5-one 19 and a number of derivatives, also investigated theoretically, prefer half-chair conformations (cf Figure 2). Molecular electrostatic potentials (MEPs) obtained by theoretical studies (CHEC-II(1996)) of certain derivatives of 17 and 18 were included in structure/antimalarial activity correlations however, distinct conclusions between MEPs and antimalarial activities were not drawn. 

The geometry of artemisinin 17, optimized at the B3LYP/6-31G level of theory, has been reported and is in excellent agreement with the X-ray structure <1997CPL(277)234> the overall structure of the 1,2,4-trioxane subsystem in 17, predicted in this study, is close to the twist conformation of 1,2,4-trioxane 21 (cf. Figure 2). 

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