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. Author manuscript; available in PMC: 2024 Mar 5.
Published in final edited form as: J Med Chem. 2021 Jul 26;64(15):10934–10950. doi: 10.1021/acs.jmedchem.1c00291

SCHEME 2. Synthesis of macrocyclic analogs of DB-310 with P3-proline substitutions.

SCHEME 2.

Reagents and Conditions: (a) Allyl methyl carbonate, Pd(PPh3)4, THF, 60 °C, 3 h; (b) TFA, DCM, rt, 1 h then evaporated and dried, N-Boc proline derivative, HBTU, HOBt, DIPEA, DCM, rt, 18 h; (c) 1. TFA, DCM, rt, 1 h then evaporated and dried; 2. alkenyl carboxylic acid, HBTU, HOBt, DIPEA, DCM, rt, 18 h; (d) 1. Grubb’s second-generation catalyst, toluene, 90 °C, 1 h, purified by flash column chromatography; 2. H2, Pd/C, methanol, rt, 1 h; (e) Amine deprotected epoxyketone (4a), HBTU, HOBt, DIPEA, DCM, rt, 18 h.