Merging Continuous Flow Technology, Photochemistry and Biocatalysis to Streamline Steroid Synthesis

Abstract

Since their structural elucidation in 1935, the introduction and substitution of functional groups and the modification of the steroidal scaffolds have been a fertile ground of research for synthetic and medicinal chemists. The discovery of steroids with hormonal and pharmacological activity has stimulated tremendous efforts to the development of highly selective and efficient synthetic procedures. Despite the progress made, steroid chemistry remains challenging and the preparation of steroidal compounds of pharmaceutical interests and in clinical practice, often requires long and elaborated synthesis. In recent years, a new impetus in the field came with the advent of enabling chemical technologies, such as continuous flow chemistry, which are exploited to overcome problems that arise from batch synthesis. Although it is still a niche sector, the use of flow technology in steroid synthesis and functionalization holds the premise to empower methodology development and to provide innovative tactics also for many hitherto uncharted chemistries. In this review, scientific contributions are reported and discussed in terms of flow set‐up and advantages offered concerning process efficiency, optimization, waste minimization, safety improvement, easy scale‐up and costs. We also highlight the main challenges, key improvements and the future trajectory in the application of continuous flow chemistry and its implementation to different disciplines such as photochemistry and biocatalysis with the ultimate goal of streamlining steroid synthesis.magnified image

Continuous Flow Chemistry: A Novel Technology for the Synthesis of Marine Drugs

“…phenol deprotonation, potassium trimethylsilanoxide (12) was loaded into a syringe w (11), while the alkyl bromide (13) was loaded into a second syringe to be pumped in reaction loop. The final step was the deprotection of the compound (14) with TFA. A could not be carried out in DMF, another step was necessary to change the solven The first total synthesis was reported in 2009 by Ullah and Arafeh using a traditional batch approach [33].…”

“…It is also possible to carry out an in situ analysis of the reaction outcome by installing analytical techniques (IR and NMR spectroscopy, and MS) or even subsequent purification systems (e.g., flash chromatography and HPLC). Furthermore, novel synthetic techniques such as photochemistry, electrochemistry, or artificial intelligence can be implemented, which overcome some limitations found in the batch mode [14]. Automated systems have also been reported in continuous flow chemistry.…”