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dipeptide synthesis strategy

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The papers which used LiHMDS or NaH had modest yields (in the ballpark of 30%), despite coming from labs with experienced synthetic chemists.  The fourth edition of Greene and Wuts present a table of half lives for removal of FMOC.  20% piperidine is 6 seconds and 50% DIPEA is 10.1 h.  I would suppose that DIPEA is slightly slower to remove FMOC than TEA, but TEA does not appear in their table on p. 713.

Given that I found one successful use of DBU to make an acrylamide (which is within shouting distance of a vinyl sulfone in terms of reactivity), I also wonder if the key to success is to consume the base more quickly in removing the proton from the Horner phosphonate than it removes a proton from FMOC.

I dont recall any of my SPS friends mentioning any troubles with TEA or DIPEA in peptide couplings or any other SP reactions but maybe their reactions were quicker than 10hrs.

I wonder if you could solve the possible deprotection issue by first reacting the phosphonate with 1 eq of base such as LiHMDS and then, after deprotonation, add the aminoacid aldehyde. Ive run HWE only once and I  just mixed all my stuff toghether but pre-forming the ylide might work as well


The order of addition is a good point that I had not considered.  When we use DBU, we always add the base to the phosphonate.  I will look at the order of addition used by the authors using other bases in closely related reactions.

Yes, I dont know the acidity of the phosphonate, maybe its more acidic then the Fmoc-proton. Its a good suggestion to mix the base and phosphonate first.

I wanted to return to the issue of reduction and assume for the moment that we reduce at the stage of having a BOC-protected dipeptide-like compound (right now this is strategy #2).  I was reading about solid phase synthesis of peptidyl-aldehydes in Chapter 6 of the book Fmoc Solid Phase Peptide Synthesis, A Practical Approach.  Some groups attach the peptide via a Weinreb amide-like linker.  When they reduced with LiAlH4 and hydrolyze, the linker breaks to release the peptide in the form of an aldehyde.  The authors of this chapter wrote, "As described previously (54), owing to the presence of several amide functions, the equivalent amount of LiAlH4 had to be increased with the length of the peptide."  I have not yet obtained the primary reference upon which this sentence is based, but I assume that it is a later paper.  One author of Chapter 6 is a coauthor of reference 54.  Reference 54 is "Synthesis of aldehydic peptides inhibiting renin" Fehrentz J-A, et al. Int. J. Peptide Protein Res. 26, 1985, 236-241.  PMID: 3902691  DOI: 10.1111/j.1399-3011.1985.tb03201.x
These authors used 8 equivalents of hydride (2 moles of LAH per mole of peptide) for a tripeptide, their compound 6. 

We have obtained good results with 1.5 equivalents Dibal-H for a BOC-protected amino acid-Weinreb amide; therefore, I was planning to start with this reducing agent.  What I am wondering is whether or not one could make an informed guess about the number of equivalents of Dibal-H that would be needed (offhand, I might guess 2.5 instead of 1.5).  The alternative is to make additions of this reagent empirically on the fly.

BTW, I recrystallized some dinitrophenyl hydrazine, which we use for a TLC dip.  It performs reasonably well for us, but DNP must be handled carefully. I have also heard of another reagent that detects aldehydes, but the name escapes me at the moment.


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