[SinkingTako]

I tried though it isn't great. A lot of the steps (eg step 2) are very iffy.

[Shadow]

What about the stereochemistry control?

[kriggy]

What about the stereochemistry control?

Good point I forget about it. I think if you want to torture yourself a bit then go for it

[phth]

Sinking: I think the third reaction will not have a problem with regio because the ring spacing of the different diols make it very different in energy, and it could be done with a lewis acid possibly increasing the yield instead of H: I think Zn can be used.

 The enolate with NaH will cause ~10% theoretical yield (elimination product unless in a solvent carefully chosen which stabilizes the anion making it less reactive, which is a solvent with hydrogen bond donors and low polarity.

[Mellitic]

Hey phth, I don't think you need to start from hydrocarbons, just cheap starting materials.  So your synthesis is actually a lot shorter that what you have written out here!

[Mellitic]

I'm trying for the chiral synthesis.  I dislike enolate chemistry, so I am attempting to go from a different route.  This is only my first pass attempt, but as I put my retrosynthesis down to (electronic-) paper I've realized I have the disfavored regioisomer from the Diels-Alder reaction.  Oops.  I'm going to come back and try to improve it, but other criticism are welcome.

[Alkene]

(I'm here to learn)
Why do you hydrolize acetyl groups with LiOH? Any reason to choose it instead of NaOH or other option?

Great post!

[Shadow]

Without the Diels-Alder, I think that this is a great synthesis. +1

[critzz]

I also gave it a try, but I just devised a route without really thinking about stereocontrol.
It's fun to see all these other approaches here.
I'm just not really sure about the first step..

Any thoughts?

[Altered State]

I'm just not really sure about the first step..

Any thoughts?

Maybe an enamine michael addition would work better?

[Mellitic]

(I'm here to learn)
Why do you hydrolize acetyl groups with LiOH? Any reason to choose it instead of NaOH or other option?

Great post!

Thanks!  Doing these types of problems is definitely the best way to learn o-chem!

As for why I chose LiOH, it was mostly because that's what I used in lab!  There are many cases where the difference between Li, Na, and K will give you a change in rates or selectivity.  For instance LiBH₄ reduces ketones with a ten fold rate increase over NaBH₄.  The rational I've heard for this is that the lithium binds more strongly to the carbonyl oxygen, thus activating the ketone during the rate-limiting step, addition of the hydride.  I've heard a similar argument for the hydrolysis of esters with LiOH/MeOH/H₂O.  Supposedly it forms a six-membered transition state to help activate the carbonyl (see picture).  Take this explanation with a huge grain of salt because I can't find any paper that supports this hypothesis or the fact that LiOH does have a faster rate compared to NaOH or KOH.  Maybe some of the more experienced members would know better.

[critzz]

Maybe an enamine michael addition would work better?

Yes, that would definitely help. Even the correct stereochemistry can be obtained by chosing the right amine auxaliary. 

[Dan]

Here's an enantioselective route. Though the chiral Si reagent is quite expensive...

[Mellitic]

Any thoughts?

You can probably set the first stereo-center with the right enolate, but I'm not sure about the second.  Maybe if you quench the reaction with a chiral acid you can set both!  I'm not sure about the desymmetrization with the witting reaction.  I think that dooms you to a below a 25% yield for that reaction and then getting the product pure will be a pain.

[critzz]

Hi Dan,

That seems like a nice proposal. I wonder how did you get to the Si-catalyst procedure?

I have got one question about this route though: does the Grignard reaction give a reliable yield/product here?
And by alkylating the ester you create another chiral center, so only one of the two products (si or re product) has the hydroxyl group in the right position to kick out the -OTBS-group?

I might be missing something here, so feel free to correct me!