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. 2008 Nov 7;73(21):8175-81.
doi: 10.1021/jo800923a. Epub 2008 Oct 9.

Substituent effects on the rearrangements of cyclohexyl to cyclopentyl radicals involving avermectin-related radicals

Jennifer A R Luft  1 , Tammo Winkler, Fiona M Kessabi, K N Houk
Affiliations

Substituent effects on the rearrangements of cyclohexyl to cyclopentyl radicals involving avermectin-related radicals

Jennifer A R Luft et al. J Org Chem. .

Abstract

The rearrangement of a substituted cyclohexyl radical to a cyclopentylmethyl radical on the skeleton of avermectin B1 has been investigated using density functional (UB3LYP/6-31G(d)) and G3MP2B3 computational methods. The rearrangement is preferred when highly radical stabilizing groups are present at the 2- and 3-positions of the cyclohexyl radical. A substituent on the 3-position of the cyclohexyl radical enables ring-cleavage of the cyclohexyl radical, while a radical stabilizing substituent on the 2-position of the cyclohexyl radical stabilizes the final cyclopentylmethyl radical, enabling the overall rearrangement and reversing the normal thermodynamic preference for the hexenyl radical ring closure.

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Figures

Figure 1
Figure 1
The two chair conformations of fused siloxycycle-cyclohexyl radical, 12a.
Figure 2
Figure 2
Potential energy surface of rearrangement from cyclohexyl radical to cyclopentylmethyl radical for 9, 19, and 21 (relative free energies at UB3LYP/6-31G(d) in kcal/mol).
Figure 3
Figure 3
Potential energy surface of rearrangement from cyclohexyl radical to cyclopentylmethyl radical for 23 and 24 (relative free energies at UB3LYP/6-31G(d) in kcal/mol).
Figure 4
Figure 4
Rearrangement of cyclohexyl radical to cyclopentylmethyl radical for model system 24 (relative free energies at UB3LYP/6-31G(d) in kcal/mol).
Figure 5
Figure 5
Geometries and UB3LYP/6-31G(d)//UHF/3-21G(d) relative energetics (at 0K, in kcal/mol) for the rearrangement of cyclohexyl radical to cyclopentylmethyl radical for model system 28.
Scheme 1
Scheme 1
Formation of 3 (minor) and 4 (major) from reaction of 1.
Scheme 2
Scheme 2
Radical rearrangement investigated by Surzur and UB3LYP/6-31G(d) free energies (kcal/mol)
Scheme 3
Scheme 3
Possible paths for the rearrangement of a substituted cyclohexyl radical to a substituted cyclopentylmethyl radical.
Scheme 4
Scheme 4
Ring-cleavage versus 1,2-shift for formation of 2-cyclohexenone radical.
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