A systematic approach to the synthesis of androstane-based 3,17-dicarboxamides (homo- and mixed dicarboxamides) via palladium-catalyzed aminocarbonylation

• Published in: Steroids Vol. 78; no. 7; pp. 693 - 699
• Main Authors: Kiss, Mercédesz, Pálinkás, Noémi, Takács, Attila, Mahó, Sándor, Kollár, László
• Format: Journal Article
• Language: English
• Published: NEW YORK Elsevier Inc 01.07.2013; Elsevier
• Subjects: 5-alpha Reductase Inhibitors - chemical synthesis; 5-alpha Reductase Inhibitors - chemistry; Androstane; Androstanes - chemistry; Biochemistry & Molecular Biology; Carbonylation; Carboxamide; Catalysis; Endocrinology & Metabolism; Ethylene-ketal; Iodo-alkene; Life Sciences & Biomedicine; Molecular Structure; Palladium - chemistry; Palladium catalyst; Science & Technology; Ethylene-ketal; Carboxamide; Carbonylation; Palladium catalyst; Androstane; Iodo-alkene; FACILE SYNTHESIS; PHENOLS
• ISSN: 0039-128X; 1878-5867
• DOI: 10.1016/j.steroids.2013.02.013

3,17-Dicarboxamido-androst-3,5,16-triene derivatives possessing various amine moieties, such as tert-butylamine, pyperidine and methyl alaninate, were synthesized using palladium-catalyzed homogeneous carbonylation as key-reaction. All variations of the homo- and mixed diamides were synthesized from androst-4-ene-3,17-dione via protection of the appropriate keto functionalities, transformation of the keto groups to iodo-alkenes and aminocarbonylation of the corresponding 17-iodo-16-ene and 3-iodo-3,5-diene moieties. •Novel androstane-based 3,17-dicarboxamides were synthesized.•Systematic investigation on the synthesis of homo- and mixed diamides was carried out.•The products are potential 5α-reductase inhibitors of pharmacological importance.•High-yielding aminocarbonylation was used as key-reaction in the multistep synthesis. 3,17-Dicarboxamido-androst-3,5,16-triene derivatives possessing various amine moieties were synthesized under mild conditions using palladium-catalyzed homogeneous aminocarbonylation as key reaction. Compounds containing the corresponding iodoalkene functionalities, i.e., 17-iodo-16-ene and 3-iodo-3,5-diene structural motifs, were used in the aminocarbonylation and the N-nucleophiles were varied systematically. Three amines, such as tert-butylamine, piperidine and methyl alaninate were used as N-nucleophiles in the aminocarbonylation. All variations of 3,17-dicarboxamides were synthesized using this methodology. Androst-4-ene-3,17-dione was used as starting material. The synthetic strategy of the multistep synthesis was based on the systematic variation and consecutive use of three different reactions: (i) the protection/deprotection of one of the keto functionalities (3-one or 17-one) as ethylene ketals, (ii) the transformation of the other keto group to iodoalkene functionality via its hydrazone, and (iii) palladium-catalyzed aminocarbonylation of the iodoalkene functionality.