[beardy]

Final assignment was a synthetic project. I was tasked with synthesizing the following compound starting from a 4-carbon chain or less.

This is my proposed synthesis. I don't know if the original beta-lactone reactant will appropriately react with the acetoacetic ester through a 1,4 michael addition because of the attached halogen. I don't know if this even matters. Feedback is appreciated.

Thank you,
beardy

[beardy]

Update

[orgopete]

I think you are running into a lot of problems. As I just looked at this, what would happen if you coupled acetoacetate and malonate with the appropriate chains and treated that product with LDA?

[beardy]

I noticed that too. I think the followup synthesis fixed that issue.

[orgopete]

You are still making this harder than it needs to be. I doubt you will be able to make the ortho ester and do a Michael addition to it. That won't be necessary. I think the connections can be made whether through a direct alkylation or Michael addition. If you reverse the steps, Michael addition is no longer necessary. You can use ethoxide with malonate or acetoacetate.

I hadn't thought through about a reduction needed. However, I think you are correct that doing it from an enol will give the correct oxidation state. If this is made into an alcohol, then you just need to finish with a lactonization.

I would suggest leaving the lactone formation to the end as it may be difficult to maintain it in your intermediate reactions.

[beardy]

Thanks for your input.

[discodermolide]

Surely that enol is an anti-Bredt structure and as such won't be formed?

[phth]

Fact: β-lactones are almost identically as stable as δ-lactones  http://euch6f.chem.emory.edu/ringclosurekinetics.html

[beardy]

 Am I wrong to use these initial reactants?  The michael acceptor is symmetrical, so am I able to use 1 equivalent of methoxide/base? Does it even matter? Would ring strain truly open the lactone during the course of the reaction? Can I use two 2 equiv of LDA in the second step?

[beardy]

Fact: β-lactones are almost identically as stable as δ-lactones  http://euch6f.chem.emory.edu/ringclosurekinetics.html

Ty for source

[orgopete]

Fact: β-lactones are almost identically as stable as δ-lactones  http://euch6f.chem.emory.edu/ringclosurekinetics.html

I only skimmed this reference, so perhaps I missed the stability issue. I did see the rates of formation were the same, but I didn't see the rates of reaction. This would be my intuitive thinking. The ring strains should be similar for the lactams and therefore if this predicted stability, they should be similar. Yet we know the beta-lactams are nature's acylating agents while the others are not.

If the lactones should be even more reactive, then carrying a beta-lactone through several synthetic steps could be a problem.

Obviously, the paper shows that if lactone formation were planned at a late stage, the rates and yields would not be limited.

@Beardy
Will the malonate anhydride be stable to NaOMe?

[beardy]

http://pubs.acs.org/doi/abs/10.1021/ja301867s

Abstract:
"Malonic anhydrides decompose at or below room temperature, to form a ketene and carbon dioxide."
"Methylmalonic anhydride is the fastest, with the lowest ΔH⧧, and dimethylmalonic anhydride is the slowest."

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Seems like the malonic anhydride is sensitive to water. Could use LDA instead? Maybe I could change one of the carbonyls on the malonic anhydride to something else

Patent abstract: http://patentimages.storage.googleapis.com/pages/US4360691-0.png

[Shadow]

I would abandon the malonic anhydride route as the anhydride is unstable. I would rather suggest this:

-the starting reagent could be made from a condensation with glyoxal
-the reduction after iodolactonzation could happen with Bu₃SnH maybe

[beardy]

Thanks for your input Shadow. I appreciate the proposed synthesis. I'm trying to understand the 1st step and iodolactonization/CHN2

[Shadow]

Iodolactonization is a versatile reaction for synthesizing lactones. DA is for Diels-Alder. (4+2 cycloaddition).