Biocatalytic Steroidal 9α‐Hydroxylation and Fragmentation Enable the Concise Chemoenzymatic Synthesis of 9,10‐Secosteroids

Abstract

9,10‐Secosteroids are an important group of marine steroids with diverse biological activities. Herein, we report a chemoenzymatic strategy for the concise, modular, and scalable synthesis of ten naturally occurring 9,10‐secosteroids from readily available steroids in three to eight steps. The key feature lies in utilizing a Rieske oxygenase‐like 3‐ketosteroid 9α‐hydroxylase (KSH) as the biocatalyst to achieve efficient C9–C10 bond cleavage and A‐ring aromatization of tetracyclic steroids through 9α‐hydroxylation and fragmentation. With synthesized 9,10‐secosteroides, structure‐activity relationship was evaluated based on bioassays in terms of previously unexplored anti‐infective activity. This study provides experimental evidence to support the hypothesis that the biosynthetic pathway through which 9,10‐secosteroids are formed in nature shares a similar reaction cascade. In addition to the development of a biomimetic approach for 9,10‐secosteroid synthesis, this study highlights the great potential of chemoenzymatic strategies in chemical synthesis.

Recent developments in the enzymatic modifications of steroid scaffolds

“…Recently, Liu and coworkers employed KSH as an efficient biocatalyst to cleave the C9-C10 bond and aromatize the A-ring of steroids, by C-9α hydroxylation and a fragmentation cascade. 80 Investigation of the substrate scope revealed the acceptance of a broad range of dienone steroids with variable C-17 side chains to generate the corresponding 9,10-secosteroid products (44 to 49) (87-97% yield). In addition, KSH mainly converted the non-dienone substrates that lack the C1-C2 double bond to the corresponding C-9α hydroxylated products (50 to 52) (64-94% yield) (Fig.…”