The first series of VHL-CRBN PROTACs (Figure ) comprises of compounds 7a,b and 14a-e. Compounds 6a and 6b, bearing respectively a 2 and 4 PEG unit linkers, were synthesized as previously reported. Briefly, triethylene or pentaethylene glycol were first converted to monobenzyl ethers and then reacted with tert-butyl bromoacetate under biphasic conditions to yield linkers 4a-b in good yields (SI Scheme 1). After deprotection of the benzyl group by catalytic hydrogenation, the primary alcohol was oxidised to carboxylic acid and subsequently coupled with VHL ligand 1, as described, to afford compounds 6a-b (SI Scheme1). Deprotection of the tert-butyl group in acidic condition followed by coupling with CRBN ligand 3 afforded the final PROTACs 7a-b in 95% and 84% yield, respectively (Scheme 1). For the synthesis of PROTACs 14a-e, symmetric linkers 12a-e bearing two terminal carboxylate groups were designed with different length and composition. Compounds 12a-e were prepared starting from the corresponding diols 10a-e. Diol 10b-e were commercially available, instead 10a was synthesized in house by adapting a previously reported method. Briefly, 10a was obtained after a nucleophilic substitution reaction between the tosyl derivative of a monobenzyl protected 1,5 pentadiol and ethylene glycol in a 2:1 ratio, followed by deprotection of the benzyl group by catalytic hydrogenation (SI Scheme 2). Nucleophilic substitution in phase transfer catalysis of diols 10a-e followed by deprotection in acidic conditions, based on our previously reported synthetic route, delivered compounds 12a-e (SI Scheme 3). Subsequently, mono N-hydroxysuccinamide ester derivatives of 12a-e, obtained via reaction with N-hydroxysuccinimide (NHS) and N,N'-dicyclohexylcarbodiimide (DCC), were reacted with CRBN ligand 3 in a 2:1 ratio to afford 13a-e (Scheme 2). The NHS activation of the linkers was required in order to better control the reaction and to reduce the formation of 2:1 conjugates between 3 and linkers. After removal of DCU side product by filtration, the 1:1 conjugates 13a-e were subsequently coupled with 1 to obtain the final PROTACs 14a-e in 42-62% yields (Scheme 2).