Synthesis of novel pregnane-based 20-carboxamides via palladium-catalysed aminocarbonylation

Abstract

Abstract20-Carboxamidopregnene derivatives, such as 3β-acetoxy-5α-pregn-20-ene-20-carboxamides and 5α-pregn-20-ene-20-carboxamides were synthesized from the widely accessible 3β-acetoxy-pregn-5,16-dien-20-one (PDA) using selective hydrogenation, hydrazine and iodoalkene formation, as well as palladium-catalysed aminocarbonylation. The 20-iodo-20-ene derivatives, obtained from the corresponding 20-keto derivatives via their hydrazones, served as substrates. 23 new 20-carboxamides were obtained using various N-nucleophiles ranging from simple primary amines to α-amino acid esters. The novelty of this methodology lies in the application of facile, moderate or high-yielding reactions to obtain otherwise hardly accessible steroidal 20-carboxamides of pharmaceutical importance. In other words, instead of the enzymatic or synthetic degradation of e.g., sterols or cholanic acids, functionalization of the basic skeleton (a ‘building-up’ approach) was used.

Carbon Monoxide as C1 Building Block in Fine Chemical Synthesis†

“…The same authors reported the aminocarbonylation of steroidal substrate pregna‐20‐iodo‐20‐ene, [ 87 ] prepared also from its corresponding 3α‐acetoxy‐pregna‐5,16‐dien‐20‐one by Barton's method (Scheme 36). The iodoalkene functionality was aminocarbonylated with several primary and secondary amines as N ‐nucleophiles, using Pd(OAc) 2 /PPh 3 as catalyst and 1 bar CO, in the presence of triethylamine as base.…”

27 Years of Catalytic Carbonylative Coupling Reactions in Hungary (1994–2021)

“…20-Carboxamidopregnene derivatives, such as 3β-acetoxy-5α-pregn-20-ene-20carboxamides and 5α-pregn-20-ene-20-carboxamides were synthesized from the corresponding iodoalkenes and various N-nucleophiles (Figure 17). The iodoalkenes were produced in multistep reactions, namely selective hydrogenation, the reaction of the subsequent ketones with hydrazine, and the conversion of the hydrazones to iodoalkenes with iodine [78]. 17-Formyl-androst-16-ene and its analogues were synthesized from the corresponding 17-iodo-16-ene derivatives in Pd-catalyzed formylation reactions in the presence of CO. Tributyltin hydride served as a hydrogen source.…”