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Chemists Present Innovative Methods For Reducing Alkenes And Coupling Them Directly

Organic Chemistry: First-row transition-metal-catalyzed processes build motifs in medicinally active molecules

by Carmen Drahl
January 17, 2014 | A version of this story appeared in Volume 92, Issue 3

Credit: Courtesy of the Baran Lab
Phil S. Baran’s team at Scripps Research Institute California has developed a direct coupling of olefins that typically takes place in less than one hour. This is an example of the reaction that takes five minutes (video is sped up with a timer for ease of viewing.) This video first appeared on the Baran group’s blog, “The Open Flask.”

Alkenes are incredibly common in the molecular world, so researchers constantly seek more ways to use them in chemical transformations. Now, two independent teams have uncovered new alkene reactivity after activating olefins with first-row transition metals. The methods—a selective alkene reduction and a carbon-carbon bond formation—each solve a problem chemists commonly face.

The advances come from the groups of Ryan A. Shenvi and Phil S. Baran, both at Scripps Research Institute California. Both chemistries convert an alkene starting material to a reactive species, explains Erick M. Carreira of ETH Zurich, who has also worked in this area. But from there, he adds, “each brilliantly utilizes the ensuing reactive intermediates in different and innovative ways.”

Shenvi’s group developed an alkene reduction that leads to alkane products with thermodynamically favorable configurations (J. Am. Chem. Soc. 2014, DOI: 10.1021/ja412342g). Alkenes are most often reduced through catalytic hydrogenation, which typically involves delivery of H2 to the same face of the alkene. The resulting products may be more accessible, but they’re not necessarily the more stable reaction product nor the desired one, points out organic chemist Michael J. Krische of the University of Texas, Austin. Reductions with a metal such as lithium dissolved in liquid ammonia provide thermodynamic products but obliterate nearby functional groups.

To get thermodynamic control without the mess, Shenvi’s team avoided the unstable intermediate that dissolving metal reductions produce—radical anions. “If you can in essence add a hydrogen atom to an alkene, your intermediate becomes a carbon radical, which is more stable than a radical anion,” Shenvi explains. To reduce the alkene, his group used a combination of phenylsilane and a manganese catalyst. They added tert-butyl hydroperoxide to their reaction to regenerate the catalyst. The method works on heterocycles frequently seen in drug molecules and also leaves nearby halogen atoms intact. Shenvi’s group is working on an asymmetric version of the chemistry and investigating its mechanism.

Meanwhile, Baran and his group developed their own variation on the alkene activation theme. They coupled unactivated alkenes to electron-poor alkenes directly (J. Am. Chem. Soc. 2014, DOI: 10.1021/ja4117632). The reaction typically takes place in less than one hour in an open flask and can be performed on gram scales. The chemistry generates crowded bicyclic molecules and quaternary centers, which are otherwise hard to construct. “The fact that a simple iron catalyst can be used to promote these transformations makes this method especially attractive,” Krische says.

Baran notes that both his work and that of Shenvi, his former student, build on a rich legacy of olefin functionalization from multiple teams. This field, he says, is poised for a renaissance.

Baran also speculates that the flavor and fragrance industry might be interested in the chemistry. “Some of our products smell really good,” he says.

This scheme shows the olefin redox reactions, two different ways.


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