Synthetic approaches for the synthesis of a cytostatic steroidal B–D bilactam

• Published in: Steroids 2003-09, Vol.68 (7), p.659-666
• Main Authors: Koutsourea, Anna I., Arsenou, Evaggelia S., Fousteris, Manolis A., Nikolaropoulos, Sotiris S.
• Format: Article
• Language: English
• Subjects: Androstenedione - analogs & derivatives; Androstenedione - chemical synthesis; B,D-bilactam; Beckmann rearrangement; Biological and medical sciences; Fundamental and applied biological sciences. Psychology; Homo-aza-steroids; Indicators and Reagents; Lactams - chemistry; N-Benzoyl protection; Oximes - chemistry; Steroidal synthesis; Vertebrates: endocrinology
• ISSN: 0039-128X; 1878-5867
• DOI: 10.1016/S0039-128X(03)00095-3

A new synthetic procedure and a modification of the original method described in the literature for the synthesis of the steroidal B–D bilactam, 3β-hydroxy-7α,17α-diaza-B,D-dihomo-5-androsten-7,17-dione are reported. The key step in the modified method involved protection of the D-lactamic nitrogen atom of 3β-acetoxy-17α-aza-D-homo-5-androsten-17-one using a reagent of specific electrophilicity (due to the stereoelectronic properties of the cyclic amide), as Beckmann rearrangement of the B-steroidal ring was hindered, possibly via long range effects, by the presence of the unprotected D-lactamic moiety. Using the 3β-acetoxy-5-androsten-17-one as starting material, a new synthetic procedure was developed through ketalization of the 17-ketone and allylic oxidation to the 7-ketone, which was subsequently followed by Beckmann rearrangement of the B- and D-steroid rings. Both approaches resulted in 45 and 67% yields of the desired B,D-bilactam, respectively, in contrast to the 15% yield, which has been reported in the literature.