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

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Abstract

Graphical abstract

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.

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.

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