in the thermal rearrangement of trioxanes 1. We aim, first,
to account for the fact that ring C of intermediate oxy
biradical 2 opens faster than ring A and, second, to
investigate how R-substituents might activate the opening
of ring A and hence provide a higher proportion of
macrocyclic lactones 7 from dispiro-1,2,4-trioxanes 1.
In order to probe the relative rates of ring opening in
species such as intermediate 2 calculations were carried out
on the putative oxy radicals 8 and 9 (Scheme 2), model
Scheme 1. Radical Rearrangement Reactions of
Dispiro-1,2,4-trioxanes 1
Scheme 2. Model Species Used in the Calculations
species for rings A and C, respectively.13 In adopting this
approach we assume the oxy radical centers in 2 will behave
independently. The computed energy profiles are presented
in Figure 1 and show a clear preference for opening ring C,
with this process having a barrier of only 4 kcal/mol, 7 kcal/
mol less than that for opening ring A. In both cases â-scission
is accompanied by the expected shortening of the carbonyl
C-O distances and a buildup of radical character at the
incipient terminal carbon, evidenced through an increase in
planarity. The breaking C-C bond is shorter in TS 9 than
in TS 8a, implying an earlier transition state in the former.
This is consistent with the lower activation barrier for ring
opening in 9 and the fact that this process is significantly
exothermic compared to the endothermic ring opening in
8a.14 Therefore, for unsubstituted models the presence of an
adjacent exocyclic oxygen strongly promotes ring opening,
and this is consistent with the experimental observation of
oxalactones 4 and hydroxyl esters 5 as the major products
in the ring-opening reactions of 1b.6
A second set of calculations was then performed to assess
the effect of R-substituents, R, on the opening of ring A,
where R ) Me (8b) or OMe (8c). In the following we focus
on isomers with R in an axial position, although analogous
calculations on the equatorial-substituted species show similar
trends (see Supporting Information). Computed activation
barriers for ring opening in 8b and 8c show a clear preference
for cleavage of the substituted C-C bond (see Figure 2).
Moreover, the presence of Me and OMe substituents
processes. In this respect, it is noteworthy that treatment of
trioxane 1b with iron(II) bromide results in the formation
of a bromoester derived exclusively from â-scission in ring
C as a major component of the product mixture; no species
relating to â-scission in ring A were reported.5 In addition,
it is known that 3-methoxy-1,2-dioxanes also readily undergo
iron(II)-mediated â-scission processes to give methyl esters.9
In a more general synthetic sense, oxy radicals have been
exploited as key intermediates in ring-expansion reactions,10
and in ring-cleavage reactions of carbohydrates.11
In this paper, we report the results of a density functional
theory (DFT) study12 of â-scission ring-opening reactions
of model cyclohexyloxy radicals analogous to those proposed
(7) Thermolyses of artemisinin and other polycyclic 1,2,4-trioxanes
generally result in extensive fragmentation of the trioxane ring and/or
intramolecular H-abstraction processes after the initial O-O bond homolysis.
See for example: (a) Luo, X.-D; Yeh, H. J. C.; Brossi, A.; Flippen-
Anderson, J. L.; Gilardi, R. Heterocycles 1985, 23, 881. (b) Lin, A. J.;
Theoharides, A. D.; Klayman, D. L. Tetrahedron 1986, 42, 2181. (c) Lin,
A. J.; Klayman, D. L.; Hoch, J. M.; Silverton, J. V.; George, C. F. J. Org.
Chem. 1985, 50, 4504. (d) Cafferata, L. F. R.; Jeandupeux, R.; Romanelli,
G. P.; Mateo, C. M.; Jefford, C. W. Afinidad 2003, 60, 206. (e) Cafferata,
L. F. R.; Rimada, R. S. Molecules 2003, 8, 655.
(8) Story, P. R.; Busch, P. AdV. Org. Chem. 1972, 8, 67.
(12) Frisch, M. J.; et al. Gaussian 03, Revision C.02; Gaussian, Inc.:
Wallingford CT, 2004. Calculations used the B3LYP hybrid functional and
6-31G** basis sets. All energies include corrections for zero-point energy.
See Supporting Information for full details.
(13) Recent theoretical treatments of â-scission in alkoxy radicals: (a)
Thiriot, E.; Canneaux, S.; He´non, E.; Bohr, F. React. Kinet. Catal. Lett.
2005, 85, 123. (b) Buback, M.; Kling, M.; Schmatz, S. Z. Phys. Chem.
2005, 219, 1205. (c) Leblanc, M.; Siri, D.; Marque, S. R. A.; Grimaldi, S.;
Bertin, D.; Tordo, P. Int. J. Quant. Chem. 2006, 106, 676. (d) Suh, I.; Zhao,
J.; Zhang, R. Chem. Phys. Lett. 2006, 432, 313.
(14) Straight-chain forms of products P 8a (E ) +2.7 kcal/mol) and P
9 (E ) -9.0 kcal/mol) are slightly more stable than the initial intermediates
shown in Figure 1 but retain the same thermodynamic preference for opening
9.
(9) (a) Murakami, M.; Kawanishi, M.; Itagaki, S.; Horii, T.; Kobayashi,
M. Bioorg. Med. Chem. Lett. 2004, 14, 3513. (b) Kawanishi, M.; Kotoku,
N.; Itagaki, S.; Horii, T.; Kobayashi, M. Bioorg. Med. Chem. 2004, 12,
5297.
(10) Sugimone, H. In Handbook of Organic Photochemistry and Pho-
tobiology; Horspool, W. M., Song, P.-S., Eds.; CRC Press: London, 1994;
pp 1229-1253 and references therein.
(11) Recent examples include: (a) Alonso-Cruz, C. R.; Kennedy, A. R.;
Rodriguez, M. S.; Suarez, E. Tetrahedron Lett. 2007, 48, 7207. (b) Alonso-
Cruz, C. R.; Leon, E. I.; Ortiz-Lopez, F. J.; Rodriguez, M. S.; Suarez, E.
Tetrahedron Lett. 2005, 46, 5265. (c) Alonso-Cruz, C. R.; Kennedy, A. R.;
Rodriguez, M. S.; Suarez, E. Org. Lett. 2003, 5, 3729. (d) Francisco, C.
G.; Gonzalez, C.; Paz, N. R.; Suarez, E. Org. Lett. 2003, 5, 4171.
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