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dipeptide synthesis strategy

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Thanks for the tip about HOAc.  My present strategies are either to couple in the presence of a Weinreb amide or to couple in the presence of a vinyl sulfone, but I prefer not to couple in the presence of an aldehyde.

Yes, that sounds logic. I dont know the stability of the Weinreb, the vinylsiulphone is a Michael-acceptor so it can be a problem with amine adding to this double-bond.

EDC byproduct is indeed readily water soluble.

NHS ester chemistry is very well defined and clean.

Right now I am leaning toward the route in which an FMOC-protected nitrogen-containing compound is made into the aldehyde, then subjected to a Horner Wadsworth Emmons reaction to make a vinyl sulfone, then deprotected on nitrogen prior to coupling.  Based upon some preliminary reading, I became concerned that our usual Horner conditions, which use DBU as the base, would be unsuitable for the FMOC-protected compound.  I realize that one could use TEA or DIPEA, which don't deprotect FMOC-protected nitrogens as quickly as secondary amines, but I did a literature search last night to seek other alternatives.  I found very similar reactions in which lithium hexamethyldisilazane (LiHMDS) or NaH were used, and those two bases will be my first two choices.  However, one reaction to produce an acrylamide did use DBU.  I have not read that paper yet, but it occurs to me that if the removal of the proton is faster than the removal of the FMOC group, this might explain their success.
Besides NaH and LiHMDS, tertiary butoxide might work, based on Reactivity Chart 8 in Greene and Wuts.  There might be an advantage in lithium over potassium as the counterion, in order to chelated the Horner phosphonate.  I have not researched this yet, and I would not try it unless there were precedent, because I am not trained in synthetic method development.  I did use potassium tertiary-butoxide successfully one time in a Horner reaction, but it was a bit of an odd duck as reactions go.

You are asking for trouble with strong base and Fmoc, if you can use TEA its a lot better.


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