[discodermolide]

I had been thinking in terms of TMS-C/NaI.  Do you mean true TMSI and not this alternate recipe?

You can use either, perhaps TMSCl/NaI is better, both are easier to handle then TMSI and the purity is better.

[Babcock_Hall]

One of my students removed the benzylester (not PMB) from benzylbutyrate last summer using TMSCl/NaI, a model deprotection study that I had forgotten about.  Also, I just found (rediscovered?) this reference:  Olah, J. Org. Chem., Vol.44, No. 8, 1979, p. 1247.  In table II reaction F is the benzylester of BOC-glycine.  The entry is a little bit puzzling, in that benzyl iodide and tert-butyliodide are listed as products, but the chemical formula for tert-butyliodide is written in a nonstandard way.  They followed the reaction by NMR and did not work up the reaction.  They used 1 hour, 25 degrees, as opposed to another group, who used 45 degrees and 0.5 hr to remove a benzylester.

I seem to recall reading that one could reflux TMSCl for a couple of hours before distilling, then distill.  Our material is a little old, so that is what I plan to do, but I cannot find a reference.  I checked Perrin's book because I thought I had read it there, but it does not seem to be.  I imagine that the refluxing step is to drive off the HCl, but I am not sure.  Does refluxing sound like a good idea?

[discodermolide]

One of my students removed the benzylester (not PMB) from benzylbutyrate last summer using TMSCl/NaI, a model deprotection study that I had forgotten about.  Also, I just found (rediscovered?) this reference:  Olah, J. Org. Chem., Vol.44, No. 8, 1979, p. 1247.  In table II reaction F is the benzylester of BOC-glycine.  The entry is a little bit puzzling, in that benzyl iodide and tert-butyliodide are listed as products, but the chemical formula for tert-butyliodide is written in a nonstandard way.  They followed the reaction by NMR and did not work up the reaction.  They used 1 hour, 25 degrees, as opposed to another group, who used 45 degrees and 0.5 hr to remove a benzylester.

I seem to recall reading that one could reflux TMSCl for a couple of hours before distilling, then distill.  Our material is a little old, so that is what I plan to do, but I cannot find a reference.  I checked Perrin's book because I thought I had read it there, but it does not seem to be.  I imagine that the refluxing step is to drive off the HCl, but I am not sure.  Does refluxing sound like a good idea?

Refluxing it can't do any harm, especially if it is an older sample.

[Babcock_Hall]

Hello Everyone,

We have continued to work on compounds similar to 5 in the drawing above.  Recently, we became aware that our deprotection conditions were giving us only a small percentage of removal of the 4-methoxylbenzylester (PMB), although the BOC group appears to be gone.  We have two related problems:

A.  How best to deprotect molecules (similar to 5) that have both the BOC group and the PMB ester.
B.  How to deprotect molecules that have already lost the BOC group but not the PMB ester.  These are likely to be a bit less soluble in some organic solvents than the parent molecule.  Yet they represent several steps of synthesis, which for undergraduates is a great deal of time invested.  In other words, it would be advantageous to get something out of what we already have, which is a set of two related molecules, one of which was synthesized twice.

I surveyed the literature on removal of this protecting group, and I would like to present a subset of that survey for clarity's sake, but I can post the rest if anyone is interested.  I assume that the scavenger picks up the 4-methoxybenzyl cation, but curiously some of the methods I examined did not include a separate scavenger, apart from the conjugate base of the acid used.  We have been using the method of Torii below.

Reference   Torii et al., J. Org Chem. 56, 3633 (1991)
Time      1 hour
Temperature   45 °C
Reagent   TFA
Mole ratio   0.5-1.0 eq TFA
Scavenger   phenol, as solvent
Work-up
Notes:  Torii et al., report less success with anisole.


Reference   Stewart, Australian J. Chem. 21, 2543 (1968).
Time      3 min
Temperature   25 °C
Reagent   TFA
Mole ratio   
Scavenger   PhOMe
Work-up

I am puzzled by the shorter reaction time and lower temperature of Stewart's method versus Torii's method, inasumch as I thought that phenol was a better scavenger than anisole.  BTW in a related thread:  http://www.chemicalforums.com/index.php?topic=67894.msg244548#msg244548 the suggestion of using 1,4-dimethoxybenzene as a scavenger in this sort of deprotection was made.

On a related matter (and in response to a suggestion upthread), we thought about trying to alkylate the pyridine nitrogen in our compounds with free omega-iodocarboxylic acids, but we ran into some difficulty attempting to purify one of them, and so we set this approach aside for now.

At this point, I am leaning toward taking a simple PMB ester or possibly molecules in class B above, and using TLC or some other method to establish new conditions to remove the PMB ester.  Of course, the conditions cannot be so forcing that they break the amide bond in the middle of our target molecules, but that is the only constraint I can think of.

[discodermolide]

Try DDQ in DCM with 4A sieves at 20°C then a basic work-up. I have a method(s) relating to discodermolide.

[Babcock_Hall]

I seem to recall seeing DDQ for the removal of PMB ethers, but I had not considered it for esters.