Coupling on N-Boc-L-valine (I) with 3-bromopropylamine (II) by means of HBTU afforded amide (III). After Boc group cleavage in (III) using trifluoroacetic acid, the resultant amine (IV) was coupled with N-Boc-L-tyrosine (V) to yield the dipeptide amide (VI). Intramolecular cyclization of (VI) to produce the macrocycle (VII) was achieved by treatment with cesium carbonate in the presence of tetrabutylammonium iodide. Subsequent acid cleavage of the Boc protecting group of (VII) furnished the intermediate amine (VIII).
The known N-Boc-hydroxyester (IX) was deprotected with trifluoroacetic acid to give (X). This was then coupled with the N-acetyl dipeptide (XI) to yield (XII), which was hydrolyzed by means of LiOH to provide carboxylic acid (XIII). The title compound was then obtained by HBTU-mediated coupling of acid (XIII) with the intermediate amine (VIII).