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Depsipeptide coupling problem (ester cleavage)

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#1 MGDrzyzga@brandeis



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Posted 19 February 2014 - 01:40 PM

I ran into an issue when coupling a carboxylic acid to an amino ester (N-methyl phenylalanine derived, if it matters). But during the procedure, the ester was cleaved before the reaction finished. I isolated the alcohol produced from this cleavage, and its NMR is identical the alcohol I'd used a couple steps ago - so I'm 100% this is going on. Questions are: why, and how can I fix it?


My conditions:

- 0.46 eq HOBt

- 4.6 eq EDCI

- DCM, rt, o/n

- NO added base. Decomposition was observed whether or not I basified the amine before treatment. I know this is unusual, but it's what was done in a very similar literature example. (Spongidepsin total synthesis. My group is borrowing the method in J. Cossy's paper, but with a new approach to the fragments, and the alkyne not installed later from a TBS ether. In other words, this step is identical except for a terminal alkyne in place of TBS ether at a distant location).


I looked up papers on depsipeptide couplings, and this method seemed quite common, though even more (and higher yielding reactions) were:

- 2 eq DIEA

- 1.5 eq HATU

- DMF, occasionally DCM or acetonitrile

- 0 C -> rt, 1 hr


I'm currently making more of my intermediates so I can try the coupling again, most likely using other conditions (like the one I found). But I don't understand why this might be a problem, and what these different conditions might be doing to actually fix things. Also, is there really any practical difference between deprotecting the Boc-amine just before coupling and using it crude, vs isolating the amine as a separate compound? I find it surprising that the first procedure traditionally uses an amine straight out of acidic reaction without any base present in the reaction.


Thoughts? Thank you very much.

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