diketopiperazine synthesis found
After a bit of digging, I found a published synthesis for a library of diketopiperazines with the same substitution pattern as in our anti-malaria candidates. My initial guess was pretty close and the published synthesis answered some of my concerns.
1) They do use a reductive amination step but not at the last step to avoid having to do the cyclization with a secondary amine.
2) The cyclization is not used to cleave from the solid support. Instead the dipeptide is freed then cyclized in refluxing toluene.
Details can be found on page 571 of this review article. The original article is here Gordon, D.W. and Steele,J. Biomed. Chem. Lett. 1995, 5, p. 47.
Next step on this project: Find a commercial source for the 2 boc protected amino acids, the aldehyde, the resin and necessary reagents. Place each one in the molecule blog.