[limorn]

hello,
i will be happy if someone could answer me for the following question:
why the reaction in the file given below would give me regioselectivity and how will it give me that?
the reaction is michael addition of thionucleophiles.
this is the quote from the article.
"It was envisioned
that the thioester 14 derived from R,â-unsaturated acid
13 could be an appropriate intermediate to regioselectively
introduce a hydroxylamido functionality at the terminal carboxyl group"

thank you very much

naftaly limor

[FeLiXe]

isn't this just the regualr Michael addition: the soft nucleophile attaches to the beta position of the alpha-beta unsaturated carbonyl

[wereworm73]

The soft nucleophile can add itself to one of the carbonyl carbons, but in this case, this type of addition is easily reversible and competes against the Michael addition.  The Michael product is ultimately favored because it retains the more stable C=O bond instead of the C=C bond, which doesn't bind its pi-electrons as strongly.

[Will]

I think naftaly wants to know why the reaction is stereospecific/stereoselective.

[limorn]

what i wanted to know is why the reaction is stereospecific/stereoselective like will said does any one know?
 

[Dan]

I have an idea, but I don't have chemsketch on this comp so see if this makes sense....

OK, the Nu adds, forming the enolate.
Now draw the enolate in it's lowest energy config - remember, minimise 1,3 allylic strain, so looking at the C with the isobutly group and rest of the chain on it, the H on that C will be in the plane of the paper pointing towards the O, isobutyl sticks up, rest of chain points down.

Now, the least hindered face of the enolate is the top one (the isobutyl group is smaller than the rest of the chain) and it is the top face that is protonated.

I warn you that I do tend to miss the main point in these kind of problems, and to be honest I don't think this is a particularly strong argument - but since no-one hase suggested anything else I thought I might as well post it...

You watch, Movies will post something brilliant eventually...

[movies]

Ohh...that sounds like a challenge!  I had better break out my model kit.

I don't really have much more to add, unfortunately, and my knowledge of peptide chemistry is lacking.  One thing I would add though is that the stereochemistry is very likely under thermodynamic control since the Michael addition is probably readily reversible.  Therefore, everything can funnel to the observed diastereomer of product.  Dan's argument is really based on kinetic protonation, which may (and probably does) control the first product that is formed, but if the reaction is reversible, then the epimeric product may form over time.^*  My guess is that you can find some 6-membered ring which is formed by intramolecular hydrogen bonding in the product.  I'm very bad at identifying these sort of things however, but I bet it's there somewhere.^**  That's probably what controls the thermodynamic product.  It is possible that the kinetic and thermodynamic product are the same, however.


^* A useful experiment to determine whether the reaction is under thermodynamic control is to independently synthesize the other diastereomer of the product and then expose it to the reaction conditions.  If it converts to the epimeric compound, then the process is reversible and dominated by thermodynamics.  Cool, huh?

^** In just glancing at the molecule, it seems that most of the obvious H bonds would make a ring where the isobutyl and the CH₂SR groups are syn, which probably isn't favorable, so maybe I am missing something.

[limorn]

thank you very much that answers my question. i will try what you said. thank you very much have a nice day