Macrocycles are attractive scaffolds for the development of new bioactive compounds. They balance the target affinity and specificity associated with biopolymers with favorable physicochemical properties associated with small molecules. Central to this behavior is the shape of a macrocycle; it is a fundamental parameter that makes a macrocycle able to bind its target. Our program is geared at understanding the factors that dictate the shape and topology of macrocycles, especially the relationship between the configuration of individual stereogenic centers and planar chirality. The [13]-macrodilactones we study are composed of three four-atom planar units (two esters and an <i>E</i>-alkene) and a one-atom “hinge”. We previously evaluated stereogenic centers associated with the ester units, both on the chain attached to the ester oxygen and the carbon α- to the carbonyl. Here we evaluate the consequences of substitution at the positions allylic to the <i>E</i>-alkene, which are β- to the ester carbonyl. We are not only looking at the effect substituents have on the shape at the allylic position, but also the effect it has on the efficiency of ring closing metathesis (RCM). RCM is a common macrocyclization strategy but there are several factors that can affect the efficiency, one being sterics around the alkene. As substituents become larger and the number of substituents increases, we find a dramatic decrease in RCM yield. Here we report the effect that allylic substitutions have on the shape and topology, as well as the RCM yield of various [13]-macrodilactones.

Substitution at allylic stereogenic centers of a [13]-macrodilactone: Effects on macrocyclization efficiency and topology

251st National Meeting (2016)

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