Cyclic Ester Synthesis

[blazinfury]

I have a question about the synthesis of cyclic esters. Is there a set strategy of approaching these types of synthesis reactions.

 

For instance, in the attached synthesis, I was told to open the bromonium ion in the last step. After looking at it, the only feasible way of doing it would be for the precursor retrosynthetic step to be a Br2/H2O, followed by the OH attacking the C=O. Is that the correct approach of doing such a problem? Thanks and sorry to be a bother.

[UC]

Open the ring up and restore the bromonium ion to where you think it should be. You should see a potentially nucleophilic group. You can make it more nucleophilic by deprotonating it. Even if there is water around, this group is right on the molecule and will preferentially attack the bromonium ion...of course it might hydrolyze afterward...so maybe you should consider a different solvent.

 

If you still don't know, draw me your opened ring and Ill see if I can point it out better.

 

PS: the attack is not on the carbon you expect. If it was on the carbon you'd expect from a typical intermolecular reaction of this type, you'd have a 4 sided ring....is a 4 sided ring a very happy structure? I'd think that the induced ring strain is probably bad enough to favor the non-markovnikov product in this case.

 

A completely different way to do this would be to diazotize a terminal amine on the ring-opened structure. The attack on the resultant primary carbocation by the carboxylic acid is extremely rapid and results in ring closing. For rings up to 6 or 7 units, it tends to occur before rearrangement of the carbocation. I could dig up refs on this one if you really need. I'd tend to avoid it, since it's probably not taught in class and some profs may not even have heard of this, but it does have synthetic utility.

Edited January 21, 2009 by UC

[blazinfury]

Well I did it, but I'm not sure if its correct. CHeck it out. Thanks a lot.

pic.pdf

[UC]

Were you supposed to start with acetylene?

 

I see issues with just about all of this, unfortunately. Acetylene is not a good candidate for NaNH2/alkyl halide treatment, because you'll get additions to both ends of it. The dibromide, after the first addition, is a secondary alkyl halide, for which acetylide anions act as bases to drive dehydrohalogenation, instead of substitution.

 

For the second step, sodium will steal that bromine off of it's carbon, probably even more easily than it will reduce the triple bond. You'll end up with dimers coupled at that carbon, less two equivalents of NaBr.

 

The third step looks fine, but you didn't write in the elimination of EtOH.

 

For the last step, I don't understand why there is sodium hydride in there, nor why you are doing an anti-markovnikov hydroboration.

 

I have attached what I'm thinking was meant by opening the bromonium ion.

[blazinfury]

Although your synthesis is freakin awesome. I was wondering if for my last step, I could have done this:

1. Br2/H2O

2.TMSCl

3. NaOH

4. BH3 H2O2/OH-

5. NaH

6. HF

7. PBr3

 

Although this may look improbable due to its length, would it still accomplish the task of attaining the designated product?

 

For step 1 with the acetylene, if I wrote 1 mol, wouldn't NaNH2 then only deprotonate 1 side?

 

For step 3, wouldn't one of the -OEt's just leave since it is a good leaving group when attached to a C=O?

 

I am sorry for these errors, but I just finished orgo 1, which is probably why some of my mechanisms are ineffective even though based on our understanding we were told they were ok. Sorry.

[blazinfury]

Either way I re-did it. Hope it is more or less correct. Sorry to takeup your time.

 

Thanks so much.

synth.pdf

[UC]

Even if you use just one equivalent of NaNH2, the deprotonatuion won't be clean. You will have a mix of mono and disubstituted acetylenes along with unreacted acetylene.

 

Maybe we didn't cover whatever the sodium hydride was used for in class, and I haven't seen it elsewhere. Br2 in H2O is pretty bad at making bromohydrins, jsut because the bromide is right there when the bromonium ion forms. A better route is N-bromosuccinimide in 50:50 dimethyl sulfoxide/ water.

 

After the bromohydrin formation, you use TMSCl. I assume this is to make a TMS-ether out of the alcohol which is on the second carbon from the end. NaOH is to eliminate the Br from the terminal carbon and make a TMS-trapped enol ether. You will get SN2 substution of the Br by OH before you get elimination. I would reccomend a very powerful non-nucleophilic base instead. Then you have anti-markovnikov hydroboration to give a primary alcohol. At this point, I'm not so sure...I suspect you are using the NaH to close the ring, cleaving the silyl ether and using PBr3 to make the free OH into Br.

 

That last bit is really unnecessarily roundabout. Heating with a moderate strength acid will drive the ring formation since 5 and 6 membered rings are very stable.

 

__________________________________________________________________________________________________________

 

Alright, had a look at your last PDF, and it looks very nice! You may want to substitute the Na in NH3 for a semi-poisoned hydrogenation catalyst and hydrogen. The classic one is called Lindlar's catalyst and I believe Pd on BaSO4 is also acceptable. A birch reduction (an alkali metal in liquid ammonia) is rather less pleasant that catalytic hydrogenation and both furnish the same product here.

 

http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv8p0606

 

You should probably use this instead of acetylene so you make sure you only get the monosubstituted product. I think K2CO3 in methanol will remove it and restore your terminal alkyne. That 1-bromoethanol you start off with is going to spontaneously eliminate HBr and form acetaldehyde, but if you can make the TMS protected form by some roundabout way, it will probably work.

 

Potassium hydride seems overkill to make the potassium carboxylate. KOH or K2CO3 should be sufficient.

 

And thinking through stuff like this is practically a hobby, so don't apologize.

Edited January 21, 2009 by UC

[blazinfury]

Thanks so much. I greatly appreciate your response. Although I do not know the mechanisms of all of the reagents that you told me about at this point, it sets a precedent in my mind to be more vigilant in future synthesis to ensure that I only get 1 desired product in greater yield. Thanks so much once again. I greatly appreciate your help in steering me in the right direction.