Sigman and Sarpong study cyclization statistically

Kim, S.F.; Liles, J.P.; Lux, M.C.; Park, H.; Jurczyk, J.; Soda, Y.; Yeung, C.S.; Sigman, M.S.; Sarpong, R. Interrogation of Enantioselectivity in the Photomediated Ring Contractions of Saturated Heterocycles. J. Am. Chem. Soc. ASAP. 

https://pubs.acs.org/doi/10.1021/jacs.4c13999

Summary Figure:

Background:

The Sarpong lab (in collaboration with Merck) had previously identified an interesting ring contraction with piperidines. This sort of "skeletal editing" is popular right now, because changing the internal structure of drug candidates makes medicinal chemistry screening more effective. This one is particularly great because it's a saturated system, and pharma companies are trying to include a higher fraction of sp3 centers in their targets, because it's correlated with better clinical outcomes. Weirdly, the enantioselectivity of the reaction varied depending on substrate (anywhere between 0-99%). This is where the Sigman lab appears to have come in to collaborate. The Sigman lab uses data to correlate chemical properties with reaction outcomes. For example, a catalyst's steric properties can be quantified based on things like buried volume or bond angles, or the electronic properties can be quantified by calculations like natural bond order charges, electronegativity, Hammett parameters, etc. Throw a bunch of these into a computer, find a fit against a variable (for example, enantioselectivity), and you can come up with a fairly good prediction of what catalyst is going to give the best enantioselectivity for a specific reaction, plus possibly an explanation about why that catalyst might be helping. It's not a one-size-fits-all tool, but perfect for a situation like this. 

How it works:

Blue light excites the carbonyl, which leads to fragmentation of the piperidine. Then, a Mannich cyclization reforms a 5 member ring.

Initial Questions:

1. Is the chiral phosphoric acid involved in the light mediated fragmentation? It is feasible it either (a) absorbs light, then transfers over to the carbonyl or (b) pre-activates the carbonyl to make that more likely to absorb light

2. What step causes the enantioselectivity? 

3. Can you design a catalyst that gives really high enantioselectivity for a particular target?

Key Findings:

1. The chiral phosphoric acid catalyst is not involved with the ring fragmentation. It only interacts for the Mannich cyclization.

2. The enantioselective step is the Mannich cyclization, which is not reversible. If the chiral phosphoric acid doesn't interact with the substrate faster than the uncatalyzed Mannich reaction, the racemic reaction happens. Steric bulk on the acid bias the conformation, although in different ways depending on the exact substrate and catalyst.

3. Yes, they increased the enantioselectivity of a particular target from 62 % ee to 91 % ee. This would be really useful if they needed to scale up manufacturing of that particular target, when you have the resources to optimize an individual reaction. 

Takeaways: 

The exact interactions that optimize enantioselectivity vary between catalyst/substrate pairing. You can't just expect that increasing or decreasing steric bulk will do anything, you need to know where the catalyst and substrate interact and optimize that interaction. Having calculated transition states helps a lot. I still think that this kind of analysis is at its best when there is a single target that needs to be optimized, and you can throw resources at it. Fortunately, this situation describes process chemistry pretty well, and that's a fairly important area of drug development. 

Data analysis like this also works particularly well for enantioselective reactions, rather than enantiospecific reactions. Normally, you'd rather have a reaction give either 0 % or 99 % ee, because there's some switch to flip on that you have to find. With this method, all of those 30% and 40% ee reactions start to become really useful data points to figure out what makes the catalyst tick. 

Don't forget that the phosphoric acid catalyst isn't actually necessary for this reaction. Obviously, the reaction would be racemic, but checking that the reaction is actually catalyzed is always necessary, and knowing what background reactions are happening is really useful.