Scheme 2.
Synthesis of the C-16 derivatized estradiol-based PROTACs. (a) TBDMSCl, imidazole, 99% (b) LDA, C4H6Br2, THF, 45% (c) NaN3, THF, DMSO, H2O, 96% (d) 1. NaBH4, MeOH; 2. LiAlH4, THF, 35% (e) Fmoc-Gly-OH, HBTU, DIPEA, CH2Cl2, 47% (f) 20% piperidine in DMF, 67% (g) DSS, DMF, 38% (h) 1. HIF-1α pentapeptide, DMAP, DMF; 2. TBAF, THF, 47% (i) H2/Pd-C, EtOAc, MeOH, 89%.