Highly Enantioselective Iodolactonization

Significance

A highly enantioselective iodolactonization of hexenoic acids 1 and pentenoic acid derivatives mediated by a bifunctional tertiary ­aminourea catalyst is reported. Using N-iodo-4-fluorophthalimide as the I⁺ source and 15 mol% of catalyst together with a catalytic amount of ­iodine at -80 ˚C, various five- and six-membered iodo­lactones 2 can be obtained with high levels of enan­tioselectivity. For the iodolactonization of 4-phenylpent-4-enoic acid, decreasing the iodine loading from 15 to 0.1 mol% can dramatically ­improve the enantiomeric ratio from 65.5:34.5 to 95:5. The use of catalytic iodine in the reaction is critical to enhancing both the reactivity and enantioselectivity of the stoichiometric I⁺ source.

Comment

Due to the difficulty of controlling the reactivity of iodonium ion intermediates, the exploration of a highly enantioselective iodolactonization is a very challenging task. The authors envisioned that the anion binding mechanism in H-bonding catalysis could also be involved in this ­reaction. Thus, a novel approach to mediate the reactivity of iodonium ions might be possible. An iodonium ion phthalimide complex (A) was proposed for the observed stereoselectivity, where there is a tertiary amino-iodonium ion interaction and the urea-bound phthalimide anion can act as the base for the deprotonation of the carboxylic acid in the enantiodetermining cyclization step. For examples on organocatalytic chloro- and ­bromolactonization, see: B. Borhan and co-­workers J. Am. Chem. Soc. 2010, 132, 3298; W.-P. Tang and co-workers J. Am. Chem. Soc. 2010, 132, 3664.