Synthesis of constrained raloxifene analogues by complementary use of Friedel-Crafts and directed remote metalation reactions.
New constrained heterocyclic analogues, 2a,b and 3, of Raloxifene (1) have been prepared by complementary Directed remote Metalation (DreM)/Friedel-Crafts cyclization approaches. Utilization of a benzylidene-thiolactone rearrangement was successfully implemented to construct benzothiophenes 13a-c in good yields. Selective deprotection of 13a and 13b induced by complexation followed by triflation gave 18 and 23, thereby allowing efficient Suzuki-Miyaura cross coupling with borolane 16 to give biaryls 19 and 24. Treatment of 19 with BCl(3) induced an intramolecular para Fridel-Crafts cyclization and concomitant double deprotection to furnish analogue 2a, a new 5,6,6,6-(C(4)S-C(6)-C(6)-C(6)) sulfur-containing heterocycle. Exposure of 25 with excess LDA induced a DreM cyclization delivering the ortho-substituted 5,6,6,6-(C(4)S-C(6)-C(6)-C(6)) heterocylic analogue 26 in 70% yield. Similar treatment of 13c and 27 afforded 30, representing the novel 5,5,6,6-(C(4)S-C(5)-C(6)-C(6)) ring system, which was subjected to Suzuki-Miyaura cross coupling with 16 to give the biaryl 31 in 93% yield; deprotection furnished the final constrained analogue 3.
Kalinin
Alexey V
AV
Queen's University, Department of Chemistry, Kingston, Ontario, Canada K7L 3N6.
Reed
Mark A
MA
Norman
Bryan H
BH
Snieckus
Victor
V
D003510:Cyclohexanes; D004952:Esters; D007202:Indicators and Reagents; D008968:Molecular Conformation; D020849:Raloxifene Hydrochloride / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D020845:Selective Estrogen Receptor Modulators / Q000138:chemical synthesis* / Q000737:chemistry; D014025:Titanium
D003510:Cyclohexanes; D004952:Esters; D007202:Indicators and Reagents; D020845:Selective Estrogen Receptor Modulators; D020849:Raloxifene Hydrochloride; C025096:titanium tetrachloride; D014025:Titanium