title: An efficient route for the preparation of a 21-fluoro progestin-16 alpha,17 alpha-dioxolane, a high-affinity ligand for PET imaging of the progesterone receptor.
abstract: Two different synthetic routes were explored for the synthesis of fluoro furanyl norprogesterone (FFNP) 1, a high-affinity ligand for the progesterone receptor (PgR) that is being developed as a PET imaging agent for PgR-positive breast cancer. Both approaches proceed through a key intermediate, triol 5. The first approach, starting from keto-ketal 2, employed a dioxenyl group as a synthon for installing a corticosteroid side chain in keto-alcohol 4. The second approach, starting from propargylic acetate 12b, involved the application of a two-step method, a Pd(II)-catalyzed oxidative rearrangement followed by a base-catalyzed acetate rearrangement of the intermediate unsaturated acetate 13b, to generate the requisite corticosteroid side chain in keto-acetate 14b. This intermediate was further elaborated to the final product 1 via efficient dihydroxylation with potassium permangnate, furan acetalization with scandium triflate, and mesylation and fluorination reactions. The palladium-catalyzed route is considerably more efficient than the dioxene approach for the synthesis of key intermediate triol 5, and the scandium triflate-catalyzed acetalization, in particular, led to a considerable improvement in the overall yield of the endo furan acetal alcohol 16a. This route provides a major improvement in the overall yield of the final progestin target, FFNP 1.
authors.affiliation: Department of Chemistry, University of Illinois at Urbana Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
authors.forename: Dange
authors.initials: D
authors.lastname: Vijaykumar
authors.forename: Wang
authors.initials: W
authors.lastname: Mao
authors.forename: Karen S
authors.initials: KS
authors.lastname: Kirschbaum
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
mesh_terms: D001943:Breast Neoplasms / Q000000981:diagnostic imaging*; D002384:Catalysis; D002625:Chemistry, Organic / Q000379:methods*; D005260:Female; D005462:Fluorine Radioisotopes; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D009652:Norpregnenes / Q000138:chemical synthesis*; D019906:Nuclear Magnetic Resonance, Biomolecular; D010084:Oxidation-Reduction; D010165:Palladium / Q000737:chemistry; D011980:Receptors, Progesterone / Q000378:metabolism*; D013237:Stereoisomerism; D014055:Tomography, Emission-Computed / Q000379:methods
chemical_list: C470081:16,17-((1'-furylmethylidene)dioxy)-21(fluoro)-oxy-19-norpregn-4-ene-3,20-dione; D005462:Fluorine Radioisotopes; D008024:Ligands; D009652:Norpregnenes; D011980:Receptors, Progesterone; D010165:Palladium