INGENIOUS ROUTE TO INGENOL
Despite tricky structure, compound finally yields to total synthesis
Ingenol, a natural product isolated from euphorbia plants, has long been a target for synthetic chemists. Not only is it the parent compound of a class of agents with promising bioactivity, but it also has an unusual structural feature that's been extremely difficult to construct synthetically.
Various ingenol derivatives have been found to be tumor promoters, antileukemic agents, or inhibitors of human immunodeficiency virus replication. But from the synthetic standpoint, perhaps what has been most intriguing about ingenol is its "trans intrabridgehead" stereochemistry--a tricky structural arrangement that has provided a difficult synthetic challenge.
Several synthetic solutions have been devised to create the trans intrabridgehead framework, but no one had used such an approach in an overall total synthesis of ingenol. Now, chemistry professor Jeffrey D. Winkler and coworkers at the University of Pennsylvania have done just that [J. Am. Chem. Soc., 124, 9726 (2002)]. The synthesis--completed by Winkler, grad students Meagan B. Rouse and Sean J. Harrison, and postdocs Michael F. Greaney and Yoon T. Jeon--is the culmination of synthetic studies begun by Winkler's group in 1986.
COURTESY OF JEFF WINKLER
Several other groups have tried to synthesize the compound, including that of chemistry professor Leo A. Paquette of Ohio State University, but prior syntheses just hadn't worked out. "Jeff is the guy who persisted, and he's finally taken it to the end," Paquette says. "I have to give him a lot of credit."
Ingenol's trans intrabridgehead is an arrangement centered on a carbonyl bridge common to two adjoining rings. Two bonds flanking the bridge adopt a trans (or "inside-outside") orientation--one points up and the other down, which is strained because both are in the same ring.
"Some time ago, we made a molecule with the bridge oriented the other way," Paquette says. "Its esters were tested in Germany and found to be completely devoid of activity--which was quite a surprise." This suggested that the strained trans intrabridgehead arrangement plays an important role in the compound's biological activity.
The new total synthesis has 43 steps, with an average yield per step of 80%. Winkler and coworkers first converted a known enone into a simple bicyclic keto ester. They elaborated the ester into a tricyclic structure containing a key dioxenone group. They used an intramolecular dioxenone photocycloaddition--a reaction developed earlier in Winkler's group--to convert that into a dioxanone. A fragmentation reaction transformed the dioxanone into a critical intermediate with a correctly configured inside-outside intrabridgehead at ingenol's C-8 and C-10 positions. The researchers also incorporated a chlorine atom at position C-14 to facilitate subsequent formation of a dimethylcyclopropane ring. The ring was added, and the resulting tetracyclic intermediate was then elaborated into ingenol by a multistep process in which seven contiguous carbon centers were oxidized.
Winkler and coworkers developed the intramolecular dioxenone photocycloaddition reaction in the late 1980s, and they found that it led to the establishment of inside-outside stereochemistry. The researchers have since used the reaction successfully in the total synthesis of perhydrohistrionicotoxin, the first total synthesis of saudin A, and now the ingenol synthesis.-