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dipeptide synthesis strategy

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I am working out how to make one or more dipeptides in which a modified aspartate residue is at the C-terminal position.  I am tempted to start by making a side-chain Weinreb amide from a suitably protected derivative of aspartate (tertiary-butyl ester at the carboxylate group), as we have done before.  Then I would deprotect the nitrogen and form an amide bond to another protected amino acid.  I am considering buying or making N-hydroxysuccinimide derivatives of the N-terminal amino acids (I found a paper in which dipeptides were made in this manner).  Then I would reduce the Weinreb to an aldehyde and do additional chemistry to introduce an electrophile, and finally deprotect.

My first question is whether or not the N-hydroxysuccinimide choice is a good one.  My second question is whether or not I have chosen the optimal point in the synthesis to make the peptide bond.  My third question is whether it makes a difference to begin the synthesis with a derivative of aspartate that is BOC- or FMOC-protected (it would be protected at the carboxylate in either case).

The choice of protecting group itself has impact on the reaction conditions you are going to use. Fmoc is base labile therefore you cant use strong bases with fmoc. Its cleaved by piperidine and other bases. AFAIK DIPEA and lutidine are fine because the deprotection with them is quite slow.
For Boc chemistry, you are limited to non-acidic reactions. I think both are fine for making the dipeptide you want but you need to consider the steps further down the line. Im not sure what are the conditions for reduction of Weinreb but you can actually reduce N-Boc to N-methyl with hydrides which is another side-reaction to consider.

Furthermore, since you are using tbutyl ester, you cant use Boc as a protecting group for amine because both are acid labile. While it is possible to deprotect Boc in presence of tBu ester, it seems easier to use Fmoc AA which is also detectable by UV/VIS.

I would use the tButyl ester of the Weinreb and Fmoc AA (be it OSU ester or OH with activating reagents)

I can answer the third question myself, now that I have thought about it; it has to be FMOC.  In our previous work, we started with a N-BOC, tertiary-butyl protected amino acid and went through the Weinreb, to the aldehyde with Dibal-H, and then performed a Horner Wadsworth Emmons reaction to install our electrophile.  Then we deprotected the BOC and tertiary butyl groups together.  My present thinking about the peptide is to replace the protecting group on the C-terminal residue with a protected amino acid residue in two steps, then move forward as we did before.

I have been reviewing the literature of making dipeptides containing vinyl sulfones.  We still need to choose a coupling reagent, and I am focusing on three right now, based on the reading that I have done so far.  One is ED(A)C/HObt; two is HBTU, and three is using a N-hydroxysuccinimide ester.  My question is how easy or difficult is it to extract the urea by-product of EDC using water.  I have seen one protocol* in which only water was used, yet I have also seen a protocol in which 1 M HCl was used.  The latter protocol did not have a BOC-protected intermediate, but our synthesis probably will.  I would like to stay away from an acid wash, if I could avoid it.
*this protocol was for the synthesis of a tert-butyl ester, not a peptide; therefore, it may not be relevant.

I think dilute HOAc is sufficient to remove the EDC-byproduct.
I am worried about your aldehyde, you have amides/carbamates in this molecule, maybe its stable for short time, maybe not. Coupling with a hydroxysuccinimide-derivativeis very clean and fast, I think its the most convenient way if you can buy the activated aminoacid.
You are starting to get many functional groups in this molecule so heads up!


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