Linkers for the second PROTAC series (Figure ) were designed to contain a carboxylic group protected as tert-butyl ester on one side and a leaving group on the other side, which could be coupled with the phenol group on VHL ligand 2. Linkers 15a-b were synthesized as previously reported, and their alkyl iodide derivatives 16a-b were prepared by reaction of the alcohol group with Ph 3 P.I 2 reagent prepared in situ (Scheme 3). Ligand 2 was reacted with compounds 16a-b and commercially available methyl 5-bromobutanoate (16c) in the presence of K 2 CO 3 to afford 17a-c, respectively, in good yields. Final PROTACs 18a-c were obtained upon deprotection of either the tert-butyl group, in case of 17a-b, or the methyl group for 17c, and subsequent amide coupling with CRBN ligand 3, using (1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium