Kwon cuts C-C bonds close to carbonyls

Citation: Simek, M.; Mahato, S.; Dehnert, B.W.; Kwon, O. Deacylative Homolysis of Ketone C(sp3)-C(sp2) Bonds: Streamlining Natural Product Transformations. J. Am. Chem. Soc. ASAP. 

https://pubs.acs.org/doi/10.1021/jacs.4c15045

Summary Figure:

Background:

For the most part, cross-coupling chemistry is about finding new ways of making C-C bonds. Some researchers care more about finding ways to break C-C bonds. This is not an easy task, not because the C-C bond is particularly strong (~80 kCal/mol, weaker than a C-H bond at ~95 kCal/mol), but because organic molecules have an unsurprisingly high number of different C-C bonds and distinguishing between them is difficult. Additionally, the same strategies for well-established C-H activation reactions are not as effective with C-C activation.

Recently, the Kwon lab at UCLA reported a wild de-alkenylation reaction, where they cleave a vinyl group using ozonolysis. It is important to note that this is not your grandparent's alkene cleavage. In that report, after using ozonolysis to cleave one carbon of the alkene, the resulting peroxide breaks the neighboring C-C bond, cleaving the second carbon as well (see below). 

Today's paper is the sequel, where the Kwon lab found that the whole ozonolysis step isn't really necessary if you can activate a carbonyl in the same way- which is in itself a very interesting and potentially useful transformation. 

How it works:

First, hydrogen peroxide forms an acetal on the carbonyl of interest, which should theoretically be a fairly trivial process. The carbon atom starts with two bonds to oxygen atoms, and ends with two bonds to oxygen atoms, and doesn't really care if they're to the same atom. 

However, hydrogen peroxide usually comes as an aqueous solution, which means you can end up with multiple possible acetals, depending on the ratio of water to peroxide. 

The Kwon lab found that only the diperoxide was competent in the reaction. In order to make more of the right acetal, the researchers had to repeatedly azeotropically dry the reaction mixture to remove as much water as possible. I'll note they did the azeotroping by repeatedly rotovaping the solution of ketone, acetonitrile, and hydrogen peroxide, which does seem easier than setting up an actual distillation apparatus multiple times. I personally do not enjoy heating up highly concentrated peroxide solutions, but the authors "did not encounter any explosions or other safety violations during [their] investigation", so that's good. 

Once the diperoxide is formed, an iron(II) salt acts as a stoichiometric reductant to reduce one of the two peroxides. 

After the reduction, the alkoxy radical can cleave the neighboring C-C bond to generate a carbonyl and an alkyl radical. This process is thermodynamically favorable, as the broken C-C bond is weaker than the C=O bond being formed. The peroxyacid will eventually be converted to a regular carboxylic acid, using another equivalent of the reductant still present. The resulting alkyl radical can be trapped with a number of different reagents, although the authors primarily examine the scope with H atom donors (in the above example, R becomes H). 

Initial Questions and Key Findings:

1. Is it possible to generate peroxide species relevant to C-C fragmentation directly from carbonyls, without having to use ozonolysis?

A: Yes, but not by just reacting the carbonyl with hydrogen peroxide. The dry solution of peroxide is necessary to form the correct diperoxide. 

2. What structures and functional groups is this reaction compatible with?

A: Silyl ethers, sulfonamides, cyclopropanes, carbamates, alcohols, esters, and some alkenes. Notable failures include benzylic and allylic ketones (1-tetralone and nootkatone), which likely means that the extended conjugated systems have side reactivity (tetralone and nootkatone). There also are some issues with selectivity, as you might expect for this sort of reaction- if there are two possible C-C bonds to break, both of them might be broken. But hey, if you design symmetric starting materials, you don't have to worry about selectivity. 

3. Can this be applied towards the total synthesis of natural products

A: Sure, after they developed the method they made a bunch of compounds. 

Takeaways:

I still believe bond forming reactions are generally more valuable than bond breaking reactions, because combining two fragments into one is such a powerful tool for designing convergent synthesis routes. I think this is like "skeletal editing" reactions, where it is useful for diversifying a scaffold in a really weird way, allowing you to access very different chemical space from an easy to reach intermediate, which does have a lot of value. 

The major lesson from this paper is that if you can make a single reactive functional group, you can do all sorts of interesting manipulations. In this case, that means making the peroxide, and then using the instability of the weak O-O bond to activate what should be a stable neighboring C-C bond.