The iodolactonization reaction includes a number of nuances that affect product formation including regioselectivity, ring size preference, and thermodynamic and kinetic control. In terms of regioselectivity, iodolactonization preferentially occurs at the most hindered carbon atom adjacent to the iodonium cation. This is due to the fact that the more substituted carbon is better able to maintain a partial positive charge and is thus more electrophilic and susceptible to nucleophilic attack. When multiple double bonds in a molecule are equally reactive, conformational preferences dominate. However, when one double bond is more reactive, that reactivity always dominates regardless of conformational preference.
Both five- and six-membered rings could be formed in the iodolactonization shown below, but the five-membered ring is formed preferentially as predicted by Baldwin's rules for ring closure.
According to the rules, 5-exo-tet ring closures are favored while 6-endo-tet ring closures are disfavored. The regioselectivity of each iodolactonization can be predicted and explained using Baldwin's rules.
Stereoselective iodolactonizations have been seen in literature and can be very useful in synthesizing large molecules such as the aforementioned vernopelin and vernomenin because the lactone can be formed while maintaining other stereocenters. The ring closure can even be driven by stereocenters adjacent to the carbon-carbon multiple bond as shown below.
Even in systems without existing stereocenters, Bartlett and coworkers found that stereoselectivity was achievable. They were able to synthesize the cis and trans five membered lactones by adjusting reactions conditions such as temperature and reaction time. The trans product was formed under thermodynamic conditions (e.g. a long reaction time) while the cis product was formed under kinetic conditions (e.g. a relatively shorter reaction time).