Conformational complexity lets Baran boast about asymmetric amino acids

Citation:

Sun, J.; Wang, S.; Harper, K.C.; Kawamata, Y.; Baran, P.S. Stereoselective amino alcohol synthesis via chemoselective electrocatalytic radical cross-couplings. Nat. Chem. 2025, 17, 44-53. 

Summary Figure:

Background:

Over the past several years, the Baran lab has been developing electrochemical nickel-catalyzed cross-electrophile coupling reactions. These reactions work by using a nickel catalyst to take two different electrophiles and stitch them together, forming a carbon-carbon bond. The overall transformation is reductive, so it requires an electron source. In some reactions, this is an organic reductant (amines, alkenes), while in many others it is a metallic reductant (zinc, manganese, or magnesium powder). Electrochemistry can be used to control the rate of consumption of these reductants- instead of throwing metal powders into the flask, you hook up a bar of metal to an electrochemical circuit, and the electrons are  released through the circuit at the other electrode at a controlled rate. The metal bar is the anode (also called a sacrificial anode, because it is consumed in the process), and the other electrode that actually dispenses the electrons is the cathode. 

The Baran lab has also been exploiting NHP esters as radical precursors for several years. N-hydroxyphthalimide esters can be easily formed by combining N-hydroxyphthalimide and any carboxylic acid under Steglich esterification conditions (usually DCC). The N-O bond is weak and the phthalimide easily accepts an electron from either a nickel catalyst or an electrode, causing it to homolytically break and generate a carboxylate radical. That carboxylate radical can then decarboxylate, generating an alkyl radical. 

How it works:

Note that the exact mechanism of the cross-electrophile coupling reaction is not fully reported in this paper, and probably varies based on class of substrate. Recent evidence has shown that it is more likely that the initial oxidative addition occurs from Ni(I), not Ni(0), and then gets reduced from Ni(III) back down to Ni(II) before engaging with the alkyl radical. 

The stereoselectivity in this reaction is interesting, because it comes from the substrate, not a chiral ligand on the nickel catalyst. The bicyclic system is rigid and forces engagement from the convex face to provide >20:1 dr of the convex:concave face product. In this figure the authors draw the mechanism as more like an SH2 reaction, where the radical directly engages with the other aryl group in an outer-sphere mechanism, which is an unusual hypothesis. 

Initial Questions:

1. Can you use the carboxylate from serine as a radical precursor to make amino acid-like structures?

2. What types of coupling partners are compatible with this manifold?

3. Is this is a synthetically useful method for industrial chemists?

Key Findings:

1. Yes, but not directly. I have no information about their thought process, but I imagine someone looked at the carboxylic acid and really wanted to find some way to derivatize it, because it would make really interesting products. Finding this particular scaffold may have been serendipity, but more likely was a lot of literature review and/or trial and error. Kudos to the chemists for figuring it out. It's even better that this enables the synthesis of enantioenriched compounds.

2. Aryl iodides, aryl bromides, vinyl bromides, acyl chlorides, benzyl bromides, and primary or secondary alkyl NHP esters (!). Functional group compatibility includes Boc and Cbz protecting groups, ketones, boronates, triazoles, indoles, and carboxylic acids. That's a lot. 

3. Probably. Electrochemistry has huge potential for making complex systems, but also some major challenges. In terms of scope, there's a ton of potential coupling partners and compatible functional groups, plus the authors describe multiple possible systems to give a head start on optimization. They also show how the reaction can be scaled up with flow chemistry, which is a near-necessity for process-scale electrochemistry.  I suspect the best use for this chemistry may be in medicinal chemistry, where it is feasible to keep a stash of the precursor ester around, then quickly running small scale reactions to make useful serine derivatives. 

Takeways:

In some ways, this method is just an extension of previously established chemistry from the Baran lab- very similar electrochemical conditions, NHP esters again, variety of coupling partners. The scope is humongous, plus they have an extensive explosion diagram of all the things you can do with a 1,2 amino-alcohol once you've made it. Adding things like that and the scale up are nice for showing off the potential applications, but also not really necessary. 

However, the idea of using conformational bias to give stereoselectivity is fairly rare for this type of reaction, and I think it's pretty smart. It's a thought process much more common in total syntheses, where intramolecular radical reactions can be controlled by contorting the molecule into a pretzel.