Enamine enables Rawal's Diene for Diels-Alder Deliciousness
In fun news, I recently defended my PhD! I've been busy the past month with that process, but hopefully I'll be back to biweekly posts for the forseeable future.
Citation:
Shamrai, O.I.; Iermolenko, I.A.; Ostapchuk, E.N.; Leha, D.O.; Zarudnitskii, E.V.; Ryabukhin, S.V.; Volochnyuk, D.M. Shackles Off: A Kilo Scale Synthesis of Rawal's Diene. Org. Process. Res. Dev. 2025, ASAP. https://pubs.acs.org/doi/10.1021/acs.oprd.5c00039
Summary Figure:
Background:
The Diels-Alder reaction is one of the most powerful tools in organic synthesis for quickly generating complex products. In one step, you're forming two C-C bonds, a 6-member ring, the stereochemistry is controllable with robust models, and you still have an alkene as a functional group handle for further manipulations. If you're proposing a retrosynthesis and have a key cyclohexane ring, you'd be crazy not to at least consider using a cycloaddition.
When you plan out a Diels Alder reaction, one of the key parameters is making sure your coupling partners are (a) active enough and (b) have useful functional group handles for the rest of your synthesis. This is why Danishefsky's diene is one of the most useful dienes for Diels-Alder reactions.
Danishefsky's diene has two really useful things going for it. First, it has two oxygen atoms that can be used for further functionalization. When exposed to acid, the TMS protecting group is removed and the methoxy group is eliminated to form an enone. You could also do a Mukaiyama aldol with the silyl enol ether. Second, the diene reacts often and it reacts reliably. Classically, in a Diels Alder reaction you want the diene to be electron rich and the dieneophile to be electron poor. You can do an inverse demand Diels-Alder with an electron poor diene and an electron rich dieneophile, but it is important that you clearly establish with coupling partner is electron rich and which is electron poor to enable cross-reactivity. The Danishefsky diene is clearly electron rich. The two oxygen atoms work in tandem, pushing electron density into the pi system, and towards a particular position. Using consonant/dissonant analysis, we can see that the primary carbon ends up extremely electron rich, which can also be shown as the resonance structure on the right:
This means that Danishefsky's diene is about as active as you can get (it's very electron rich) and very reliable (it always gives the diastereoselectivity predicted by the model).
But what if you can go even further?
Enter Rawal's Diene
Rawal's Diene is like Danishefsky's Diene's more jacked older brother. Instead of a methoxy, it has a dimethylamine group, which is even more electron rich. Rawal's diene reacts about 25-3000 times faster than Danishefsky's diene, which makes it even better for difficult dieneophiles, like aldehydes. The fact that it has a C-N bond instead of a C-O bond ends up mattering less than you'd expect, since often it ends up eliminated anyways, but it gives some new opportunities to make interesting structures. The major problem with Rawal's diene has been the cost- as the authors note, the only reliable supplier has been Sigma Aldrich at 5 g for $420 at the time of this post. I'll note that Danishefsky's diene is also available from Sigma at a max size of 5 g for $187, which is somewhat surprising. Enter Enamine, who wanted to develop a scalable synthesis of Rawal's diene.
How it works:
The actual synthesis of Rawal's diene is fairly straightforward and robust- the authors note that the synthesis published in Organic Syntheses worked reliably with the expected purity and yield. Score another win for Org. Synth.
The overall procedure is to take an aldehyde that was protected as an acetal and condense it with dimethylamine to make the conjugated enone. Then, you deprotonate alpha to the ketone (using NaHMDS as a strong base) and trap as the silyl enol ether with TBSCl.
Enamine didn't actually change the synthesis a ton, instead making a number of small improvements (listed below)
1. Did not distill the starting material before use.
2. In the first step, instead of using methanol as the solvent, ran the reaction in water to reduce costs at no change in yield.
3. In the second step, used a more concentrated solution of NaHMDS (2 M instead of 1 M).
4. Swapped the order of addition and added the NaHMDS solution to the enaminone,
5. Changed the temperature from -78 C to -40 C.
6. Used 1.10 equiv NaHMS instead of 1.00 equiv
7. Used 1.15 equiv TBSCl instead of 1.05 equiv
8. After the reaction, diluted reaction mixture with tBuOMe and chilled for 12 h to precipitate NaCl
9. Developed protocol to quickly filter the reaction mixture to reduce exposure to air and water
Overall, these are a lot of little changes, each of which is not very important on their own but together pushes the yields into commercially useable figures. The answer to every question does not need to be "reroute" or "find a different reagent".
The last change also turns out to be really important. The authors did some studies on the sensitivity of the product, and turns out Rawal's diene is really air and water sensitive. When working with something so electron rich, it is easy for it to oxidize by oxygen in the atmosphere.
The authors kept a couple samples of the diene in different conditions. Open to air, the diene was unusable in less than a week. In a closed vial, after 7 days there was about 3% yield of an unidentified impurity (by mol) and the sample was visibly turning orange. After 14 days, it was up to 11%. When kept under argon, in the fridge at 4 C, the sample was 83% pure after 2 years, which isn't ideal but reasonable. Probably should keep your bottle in the glovebox freezer.
Surprisingly, Rawal's diene is not able to be analyzed by LCMS or GCMS, and most NMR solvents had too much water and quickly degraded the diene. The authors note you can use dry CDCl3 in a pinch, but recommend C6D6.
Finally, the authors used Rawal's diene at large scale for a couple of molecules that people had wanted to make in the past with a 4+2, but found the Diels-Alder with Danishefsky's diene difficult because it requires a Lewis acid.
Initial Questions and Key Findings:
1. Can you make Rawal's diene in a cheaper and more scalable way?
A: Yes, the authors found some subtle improvements and were able to increase the size of the largest produced batch of Rawal's diene from 20 g to 520 g.
2. Can you use Rawal's diene right out of the bottle and keep it around?
A: If you are making Rawal's diene to ship out commercially, it is important to develop a process that keeps it air and moisture free as much as possible. That means flushing the bottle with argon, probably using a sure-seal, and keeping it cold as much as possible. All of these are doable, but need to be kept in mind if you're selling this chemical.
Other References:
Kozmin, S.A; Janey, J.M.; Rawal, V.H. 1-Amino-3-siloxy-1,3-butadienes: Highly Reactive Dienes for the Diels-Alder Reaction. J. Org. Chem. 1999, 64, 3039-3052.
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