Free radicals! Everything about them sounds creepy and extreme – and it has been for a long time. In the early days of radical chemistry, high temperatures, UV light and dissolving metals were the only way to get to these often highly reactive intermediates. While these species are still a bogeyman in the advertising of many questionable health products today, they have become an indispensable tool for the modern synthetic chemist. One can only imagine the dismay of radical chemistry pioneer Moses Gomberg, who tried in 1901 to reserve her studies for himself.

During my PhD, I performed a range of textbook radical reactions, including birch-type reductions, benzylic brominations, and even some organotin chemistry that I can smell to this day. These were typical radical reactions of the old school – so pretty dangerous and unattractive. In the roughly 10 years since I graduated, however, some of the hottest research areas in organic synthesis have been those that allow us to more easily create and use open-shell species, which is the essence of most photoredox catalysis. With modern methods of generating radicals, calculating bond strengths and explaining their reactivity, we can now use these reactive but predictable species to perform powerful and unique chemistry – without having to sunburn from mercury lamps or bleach tin from all of our glassware!

A more recent total synthesis that demonstrates a number of old and new radical methods is the total synthesis of norzoanthamine by Shuanhu Gao and co-workers at East China Normal University in Shanghai.1 This complex target, one of the dubious zoanthamine alkaloids, has attracted considerable attention, but the group achieved an outstanding synthesis thanks to the skillful use of radical chemistry to set both the C12 and C22 quaternary stereocenters.

I always feel like an alchemist – or a magician

We start the synthesis while the team is in the process of setting the final quaternary stereocenter on C12. Radical chemistry is uniquely suited to the formation of often tricky quaternary carbon centers, as it easily forms tertiary radicals and is sterically not strongly inhibited. Here, a recently published cobalt-catalyzed hydrogen atom transfer (HAT) generates the desired radical under mild conditions that quickly adds to the neighboring arene to give a single product diastereomer. Next, one of my favorite reactions, the Birch reduction, brings the aryl ring to the correct enone oxidation state (Figure 1). The ink blue-black color that occurs when sodium dissolves in liquid ammonia is perhaps the closest to seeing unpaired electrons with the naked eye and always makes me feel like an alchemist – or a magician.

A picture showing a reaction scheme

Although this ring now contains the ketone and alkene found in the target, both are initially in the wrong place. The first step in fixing this is to reduce the double bond, but the challenge with this is that tetrasubstituted alkenes are notoriously unreactive. Classic hydrogenation methods are also effective syn Adding hydrogen, causing the undesirable cis Decalin ring compound. Here the radical chemistry intensifies again with a recently reported HAT reaction that I mentally call “Shenvi.” have archived Anti-Hydrogenation “(Figure 2). This unique transformation involves the stepwise addition of hydrogen atoms to an alkene and enables the configurationally flexible radical intermediate to find its most thermodynamically convenient position and selectively the desired one trans– stereochemistry.

A picture showing a reaction scheme

From here there is still a lot of work to be done on the lower half of the molecule, but with the tricky carbocyclic scaffold, the team is well positioned to succeed.


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