[zuriel]

Hey guys,

I'm completely lost on this question, does anyone have any ideas/are able to point me to relevant papers? In my University we have these problem sets every week and we get about half a day to do them - sometimes they're fine but this one is taking me a while to find plausible reactions of the materials outlined. Help would be greatly appreciated - thanks a million. 

[discodermolide]

Why don't you disconnect the product and see which reasonable fragments you get that may match up with your starting materials.
I think it looks pretty obvious, it's just getting the steps in the correct order.

[zuriel]

OK so from examining it further I can spot the following:

1 - the amide link between C and the methyl ester on B.

2 - the "amine link" between the NH2 in D and the -Cl in B.

3 - the "amine link" between the -NH in A and the thioether in B.

Am I going OK so far? I feel so dumb for not being able to spot the synthetic steps but...these kind of full synthesis questions are a new thing for me.

[discodermolide]

Well that is the way I was thinking of, so either we are both correct or both wrong

[zhangcarlin]

In my opinion, the best solution for your proble, is that you draw the synthentic route amd then check the methodlogy for the preparation of this compound in Reaxys or SCI finder. Then, you will know where you are.

[zuriel]

OK so I think I have most of it. Wikipedia had a very general route but with some of my own chemical input it looks OK. My only problem is the reaction between the -NH and the R-S-R. Is this a common reaction? I have never encountered it before - according to wikipedia the thioether functionality is first oxidised then an electrophilic aromatic substitution with the amine is undertaken. Can anyone shed any light on this? Thanks for you help so far guys!! I'll get there....eventually.

[discodermolide]

How far does the oxidation go, to the sulfoxide or the sulfone? Both should be reasonable leaving groups.

[orgopete]

I thought the chloride was the most reactive.

[zuriel]

I thought the chloride was the most reactive.

To organopete - yes the chloride reacts first with structure D as follows:

http://upload.wikimedia.org/wikipedia/commons/3/33/Avanafil_synthesis.png

To discodermolide - it goes to the sulfone!

[discodermolide]

I'll bet they tried the route we were suggesting. It may be that they had yield problems, side product problems, even thermodynamic problems, or purity issues, which is why they chose this route.

[zuriel]

OK so this is the mechanism I've deduced. Discodermolide - would you be able to have a read through this and tell me if it makes logical sense?

1 - Nucelophilic aromatic substitution between the -Cl in B and the -NH2 in D.

2 - Oxidation of the thioether to the sulfone (forming a substituent that's a good leaving group).

3 - Nucleophilic aromatic substitution with A, displacing the sulfone leaving group.

4 - Hydrolysis of the ester group followed by DCC coupling with C to afford AVANAFIL.

If you guys can spot any side products of possible side reactions/good solvents to use - let me know what you think also.

The only side products I can see so far, apart from salts etc. Are the DCU (dicyclohexylurea) from the coupling. As for solvents...DCM? Or Chloroform?

[discodermolide]

You forgot the sulfonic acid.
Solvent, well if this is the industrial synthesis, perhaps methanol or another alcohol even DMF can be used. Perhaps pyridine or N-methylmorpholine as bases to mop up any acidic impurities.

[zuriel]

Where does the sulfonic acid come into it though? Does the sulfone leaving group mop up an -OH to generate the acid as a side product? (Sorry, stupid question I know - but I need to examine the synthesis closely for any possible pedantic questions that will be asked!)

Also, I'm not sure if the lecturer made a mistake in the stereochemistry of the AVANFIL structure in the question. It seems to be (R) in the question (at the A component) but according to various pieces of literature, the (S) configuration is the one needed.

I don't understand how the stereochemistry changes there.

[discodermolide]

The sulfonic acid comes from the sulfone after it has left perhaps as a salt of a suitable base.
The (S) config is correct.In your diagram the final product should have the other stereochemistry.

[zhangcarlin]

Should I upload the synthentic route route from Reaxys?