[acarter5251]

I came across a reaction in the literature where a hydroxyl group on amphotericin B was protected using catalytic camphorsulfonic acid and methanol to yield the methyl ether.  I was just wondering what the mechanism of this involves?  I have looked everywhere and cannot seem to find anything.

Thanks in advance!

Reference to paper:
Nontoxic antimicrobials that evade drug resistance
Nature Chemical Biology 11, 481–487 (2015)

[Dan]

You are more likely to get comments if you draw out the reaction for the benefit of those who do not have access to the paper.

[acarter5251]

I'm sorry about that. Here is what is happening:

[Babcock_Hall]

Please give us your thoughts first, then people will comment.  This is a forum policy.

[acarter5251]

My thoughts are that the camphorsulfonic acid is first protonating the hydroxyl that is being protected.  Then it appears that the methanol somehow comes in to replace that hydroxyl. However, what is hanging me up is how stereochemistry is being preserved here (is it the fact that the camphorsulfonic acid is somehow forcing the methanol to come from the same side?).  Also, I'm not entirely sure why this only occurs at this hydroxyl, when there are plenty of others on the molecule (more stable due to it being tertiary?).

[phth]

Waht do you call that specific functional group that you are modifying? (hint: there are 2 in the molecule, it maybe 1 but I cannot see that well without a newman projection).  Have you learned about solvent cage?  What is protonating the oxygen camphor-SO₃H or MeOH₂⁺/THF-H⁺?

[acarter5251]

I'm not sure if this is what you meant by functional group, but it is a hemiketal.  As far as what is protonating that oxygen, I would think that it is the CSA, but I'm not sure on that either.  I have learned a little about solvent cage, but not much.

[phth]

Yes.  Hemiketals will have a different rate of hydrolysis than ROH.  What's the pKa of camphorSO₃H and the pKaH⁺ of methanol and/or THF?  You can look up the answer.

[acarter5251]

So the fact that it is a hemiketal is what leads to the selectivity of the protection step? 

pKa of MeOH2+ is about -2 vs. a pKa of about 1 for CSA, so I guess it would be more reasonable that the solvent is protonating the oxygen of the substrate? I just wasn't sure with it being a small amount of CSA in the reaction mixture.

[phth]

OKay good. I didn't recognize that it is in catalytic quantities.  Therefore, I believe it has to do with the energy of the ring system i.e. that the isomer shown is more stable than the other due to the engergetics of the large ring system.

[acarter5251]

Yeah sorry about that, the CSA is in catalytic amounts.  So what you are saying is that the conservation of the stereochemistry at the hemiketal/ketal is due to the energetics of the macrocycle?

[phth]

Yes, it is equilibrating to the formation that is more stable, and this is related to the equilibrium constant of this substitution reaction.   

[acarter5251]

Ok thanks!  Could it have to do with interactions in the molecule like the one shown in this figure (part a)?



More specifically between the mycosamine and the (hemi)ketal?

[phth]

Water is not the solvent but similar in the reaction; the conformation shown will contribute to the energetics.  You could do some calculations using software to figure out how much,  im guessing it is not larger than the ring strain, how much I'm not sure of.

[acarter5251]

Thank you so much for your help.

I have one more question.  They state that in performing their HPLC purification in 59:41 water+ 0.3% formic acid/MeCN, the methyl ketal converts back to the hemiketal. Is this essentially the same type of reaction as going from the hemiketal to the methyl ketal, but with water displacing the methoxy?