[ghovinsen]

I'm reading a paper on the synthesis of Tamiflu. The first reported (I think) on the synthesis of Tamiflu is by Kim et al (J. Am. Chem. Soc. 1997, 119, 681-690). During the synthesis, an aziridine is required to be synthesized from an azide. They employed the Staudinger reaction, if I'm not mistaken.



I've thought of the mechanism, but am not sure if it's correct. As far as I know, the Staudinger reaction does not require mesylation of the adjacent hydroxyl group.



I consider the mesylation to improve the hydroxyl group as a leaving group, which attacked by the amide in Sn2 fashion. If so, what is the purpose of triethylamine? I guess it's to quench the proton after water attacks PPh3? Any ideas are really appreciated. 

[discodermolide]

Triethylamine removes the methane sulfonic acid formed.

[ghovinsen]

Are there any harm if methanosulfonic acid is not removed?

[rolnor]

I think in the synthesis of Tamiflu the reaction is not Staudinger but a reduktion of the azide to form amine and then cyclic substitution of the mesylate to form the aziridine.

[TheUnassuming]

rolnor: staudinger is the right name, originally used for a ligation but can also be used to reduce azides to the corresponding amine.  In this case I think the formal name is the "Staudinger Reduction".

OP: Do you see any functionalities that might be sensitive to acid?

[rolnor]

Sorry, you are right. But there is a difference if you have the mesylat or alcohol, the mechanism are different?

[TheUnassuming]

I would assume much of the mechanism is going to be the same with both, at least insofar as the direction of the arrows... with a twist the OP needs to work out to get the answer to his question  

OP: be careful in your mechanism.  In your second to last structure (in your mechanism) you have a negatively charged amine (amide), which wouldn't exist in water.  So if its an amine, do you think its a strong enough nucleophile to kick out a hydroxyl group as you suggest? 

[ghovinsen]

Thanks for the suggestions! I guess methanesulfonic acid can destroy the MOM protection group. I have rewritten the mechanism. I guess the hydroxyl group is mesylated to increase the leaving group ability.

[TheUnassuming]

Good! The MOM group is acid labile, so that's probably a safe bet as well as keeping the aziridine neutral.  The Ms group will also turn the OH into a good leaving group, so I think your mechanism looks good for that substrate. 

For the original substrate that didn't use water/NEt3 though, I would bet based on the conditions shown there is a different mechanism which would explain why they had to use a Ms protected OH in this case.  Look at the mechanism you have drawn for the Ms compound, and remember that there is no water in the original substrate reaction, so that OH has to come from somewhere else.   Also important is that an alcohol by itself is generally a poor leaving group unless using specific (usually harsh) conditions.

[ghovinsen]

Thanks for the suggestion!

In the next step of the synthesis they introduced an azide group (NaN₃, NH₄Cl, DMF). The azide seems to selectively attack the C4 position instead of the C5 position. Could this be due to the steric hindrance produced by MOM-O? The introduction of azide group occurs twice throughout the synthesis.



I wonder why the two employs different solvent. Both MeOH/H₂O and DMF are polar solvents, so my best guess is they employed different solvent for to accommodate different solubilities.

[wildfyr]

I just noticed, they are using sodium azide in a reaction with an acid (ammonium chloride). Its a weak acid, but nonetheless, this can be extremely dangerous! Azide nucleophiles shouldnt be exposed to acids, alkyl halide solvents, or high heat. I wonder why ammonium chloride was needed at all?

[TheUnassuming]

Ammonium salts to act as a weak acid in combination with azides are fairly common and not all that dangerous.  The difference in pka of the two is sufficient to make the chances of protonating the azide negligible from a safety standpoint.  That said, I've always used a blast shield just in case when I've run similar reactions.

Steric hindrance probably has an effect, but maybe there are additional reasons?

[rolnor]

The acide-ffect from NH4Cl is protonating both the epoxide-oxygen and the nitrogen in the aziridine, making them open easier when NaN3 attacks.

[wildfyr]

Ah, thanks guys. to the OP, I would suggest using the bi-solvent mixture if youre looking to boost yields here, or even a completely biphasic mixture. I've run tons of azidification reactions that use Acetone/water or toluene/water and work excellently. The acetone one is nice because its a kickass solvent in general and can be rotovapped off at low temps and then replaced with ether for lovely clean workup. I've seen but never tried the same concept with ethyl acetate, which would be liquid-liquid extraction ready right out of the gate. I only suggest it because DMF can be such a pain in the ass to remove, and NaN3's solubility in it is not awesome.