Liu lops off NHP esters to form alkenes stereospecifically

Citation:

He, F.; Huang, Y.; Jiang, L.; Liu, W.H. Stereoselective Synthesis of Olefins from B-Hydroxy NHPI Esters. Org. Lett. 2025, ASAP. 

Summary Figure:

Background:

No metals today! I saw this very interesting paper on a reaction with NHP esters and thought it's a short and nice little mechanism.  

I believe the Liu lab is fairly new, but they've done some interesting work so far in photochemistry and in non-organometallic methods. A lot of their reactions look like they should have some sort of metal involved, but they're unlocking some interesting and somewhat non-intuitive mechanisms with some clever thinking. For example, the precursor to this paper turned aldehydes into olefins using an alpha-halo NHP ester (https://pubs.rsc.org/en/content/articlelanding/2024/qo/d3qo01805a): 

 

 

The idea is that you do a Reformatsky reaction: first generating the zinc enolate, which then attacks the aldehyde to form the 1,3-betahydroxy carbonyl. One thing that's neat about this is they actually draw the Zimmerman-Traxler transition state and call it out by name. Somewhere a synthesis professor is smiling.* Then, the zinc activates the NHP ester via SET to generate a carbon centered radical (which is what we usually see in organometallic chemistry), which is then reduced farther to the anion. From there, elimination of the hydroxyl group via E1CB provides the olefin: 

Or so they thought!

How it works:

At some point while finishing that project, the authors observed they could isolate the two diastereomers of the 1,3-betahydroxy NHP ester they had proposed as an intermediate. Obviously, as it was formed from the Reformatsky reaction, they did not control the diastereomeric ratio of these intermediates, so they did not see selectivity. However, it is possible to synthesize these directly, and there is a LOT of chemistry to do aldol reactions diastereoselectively and make either the syn or anti products. Again, somewhere a synthesis professor is squealing with delight.* 

After some optimization to increase the yield, when diasteromerically pure 1,3-betahydroxy NHP esters were combined with Lewis acid and heating, the diasteromerically pure alkenes were obtained. The anti diastereomer led to E alkenes in "exceptional" stereoselectivity (20:1), while the syn diastereomer led to Z alkenes in only "excellent" stereoselectivity (19:1). 

Somewhat bizarrely, the conditions for the E procedure are different from the Z procedure. To make E alkenes they use LiI in THF, while to make Z alkenes they use MgBr2 and Et3N in DMF. Unfortunately, even in the SI the authors do not subject each diastereomer to the other's reaction conditions and do not offer an explanation for the difference.

The important point here is that there is no reductant in this system. Under the previously proposed mechanism, to form alkenes from the 1,3-betahydroxy NHP ester requires SET from the zinc reductant to activate the NHP ester. 

Additionally, the authors observe 2 byproducts from the reaction: CO2 (detected by GCMS), which makes sense, and N-hydroxy-phthalimide, not just phthalimide. Normally, the byproduct from SET activation of an NHP ester is phthalimide, because you break the weak N-O bond to generate the carboxylate radical, which then decarboxylates (blowing off CO2) to make an alkyl radical. Instead, the C-O bond of the ester is cleaved in some fashion.

 

The authors propose that instead of breaking the NHP ester via a radical process, the betahydroxy group forms a lactone and kicks out N-hydroxyphalimide. They also confirm the lack of radical formation by testing with TEMPO and observing no inhibition. 

 

 

Formation of the lactone and decarboxylation are both stereospecific, which explains how the diastereoselectivity is locked in. For more information on the stereospecificity of beta-lactone decarboxylation, see the following papers, which describe the "intimate ion-pair" required for the stepwise cycloaddition: (https://pubs.acs.org/doi/10.1021/jo01350a037 and https://onlinelibrary.wiley.com/doi/10.1002/anie.198004651). Somewhere a synth prof is dancing with joy.*

Initial Questions and Key Findings:

1. Can you selectively form E or Z alkenes by using only a single diastereomer of the betahydroxy NHP ester starting material?

A: Yes, the reaction appears to be stereospecific. The conformation of the starting material directly dictates the conformation of the product. This is because it does not go through a radical process; instead, the NHP ester is a good leaving group to enable the formation of a lactone.

2. How robust is this method?

A: The substrate scope does not highlight any particularly noteworthy sensitivities. I would have liked to see a more diverse scope. 

3. Is this a superior process to make alkenes compared to previously existing processes?

A: We have a lot of really good ways to make alkenes, so not really. Notably, making Z-alkenes is significantly more challenging than E alkenes, and the advantage this reaction has is that it is stereospecific, not stereoselective. If your Wittig reaction gives low diastereoselectivity, this method would be a reasonable alternative to try, assuming you can make the syn-diastereomer in high selectivity. The authors do note "this method cannot compete with the Wittig reaction regarding robustness and functional group tolerance", but if your nearest benchmark won a Nobel prize, you're in good company. 

Key takeaways:

I highly doubt that this is the first time someone has done this reaction: given the explosion of reports using NHP esters, and the ubiquity of aldol reactions, I'm sure someone has tried a betahydroxy NHP ester as a substrate. Now we know that this is a possible decomposition pathway. 

I don't think the authors were wrong for proposing the mechanism they did in their first paper. It seems fairly feasible, although the second SET to generate the anion from the radical is somewhat suspect. Importantly, in the original report they were creating a stereoselective method, so they observed varying dr in the product. It was only after they synthesized the relevant intermediate that they discovered the second half of the mechanism is stereospecific. When you push your mechanistic understanding as far as you can go, sometimes you'll find something surprising!

*This is a lie, synth profs are never happy.