Selective aromatization of ringBin 19-norsteroids and synthesis of equilenin-type compounds

Abstract

The preparation of 7a-acetoxy-3,3:17,17-bis(ethylenedioxy) -5,l O-epoxy-SP,l OP-oestran-6-one (4) is described. When heated with alkali it undergoes ring 6 aromatization t o give 3,3:17,17-bis(ethylenedioxy)oestra-5(10).6,8-triene-6,7-diol (7), without configurational change at C( 14). Bis-deacetalization of the corresponding diacetate ( 8 ) , followed by lead tetra-acetate aromatization of ring A in the resulting diketone (9), produces 6,7-diacetoxyequilenin (1 0), which is finally converted into its 3-acetate (1 1 ). The same ester product (1 1 ) could also be obtained by conversion of the diketone (9) into its 3-en01 acetate (12), followed by lead tetra-acetate dehydrogenation.

The Fit For Purpose Development of S1P1 Receptor Agonist GSK2263167 Using a Robinson Annulation and Saegusa Oxidation to Access an Advanced Phenol Intermediate

“…tert-Butyl-5-methyl-6-oxo-3,4,6,7,8,8a-hexahydroisoquinoline-2(1H)-carboxylate (9). To a solution of N-Boc-4piperidone 8 (19.8 kg, 99.2 mol, 1 equiv) in toluene (87 L) was added pyrrolidine (10.9 kg, 1.55 equiv).…”

“…However, oxidation to phenol 4 proved more challenging. A number of aromatisation conditions including α-halogenation/elimination, benzoquinone oxidation, epoxidation/aromatisation , and Pd/C dehydrogenation were unsuccessful with acidic conditions and high temperatures resulting in undesired Boc deprotection. This prompted investigation into the Saegusa oxidation, which avoids both acidic conditions and high temperatures .…”