Modular syntesis of pyritidesOštrek, Andraž (Avtor) Svete, Jurij (Mentor) Šarlah, David (Komentor) pyritidestotal synthesisstabilized phosphorous ylidesvicinal tricarbonyls236‑trisubstituted pyridinesTotal synthesis of the pyritide A2, a natural product of the newly discovered group of pyritides, was envisioned by the Sarlah group. We have approached the synthesis of the 2,3,6-trisubstituted pyridine core, bearing two carboxylic groups and one substituent originating from arginine, with two synthetic strategies. Preliminary experiments with the Minisci-type alkylation of 3,6-disubstituted pyridine were not successful; thus, we terminated examination of this route. De novo synthesis of the pyridine ring was employed as the second route. We had to consider appropriate protecting groups for two carboxylic groups (ethyl, 2-(trimethylsilyl)ethyl and 2,2,2‑trichloroethyl protecting groups) and for both arginine-originating α-amino and guanidino groups (tert‑butoxycarbonyl and benzyloxycarbonyl protecting groups). Orthogonal protecting groups will allow selective deprotection and enable the desired reactivity of the trisubstituted pyridine in further peptide coupling reactions towards the synthesis of the pyritide A2. We started this synthetic route with the model system based on phenylalanine and translated results to the real system based on arginine. Corresponding O-protected phosphonium ylides were prepared from 2-bromoacetyl bromide in three steps and were further coupled with corresponding α-amino acid. PyAOP performed the best of the peptide coupling reagents examined, resulting in 40–83% transformation. The formed stabilized ylides were masking the vicinal tricarbonyl functionality, which could be revealed upon oxidative cleavage of carbon‑phosphorous bond. Oxidation was successful with ozone, while other oxidants did not provide practical conversions. Furthermore, one-pot reaction with corresponding amidrazone (triazine formation with condensation) and 2,5‑norbornadiene (aza-Diels–Alder reaction and rearomatization) yielded the compounds of interest. Starting from stabilized ylides, heterocyclic product of the phenylalanine-based system could be prepared in 40% yield, while the targeted arginine-based system gave 14–25% yields. Finally, the 2,3,6-trisubstituted pyridine core was accessible with the de novo synthetic route in low yields, which are expected to be improved with further optimization.20202020-09-11 16:30:04Magistrsko delo/naloga119829sl