Concise Large-Scale Synthesis of Tomatidine, A Potent Antibiotic Natural Product

• Published in: Molecules (Basel, Switzerland) Vol. 26; no. 19; p. 6008
• Main Authors: Normandin, Chad, Boudreault, Pierre-Luc
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 03.10.2021; MDPI
• Subjects: Acids; alkaloids; Antibiotics; Iodine; Natural products; Reagents; small-colony variants; Staphylococcus aureus; Steroids; tomatidine
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules26196008

Tomatidine has recently generated a lot of interest amongst the pharmacology, medicine, and biology fields of study, especially for its newfound activity as an antibiotic agent capable of targeting multiple strains of bacteria. In the light of its low natural abundance and high cost, an efficient and scalable multi-gram synthesis of tomatidine has been developed. This synthesis uses a Suzuki–Miyaura-type coupling reaction as a key step to graft an enantiopure F-ring side chain to the steroidal scaffold of the natural product, which was accessible from low-cost and commercially available diosgenin. A Lewis acid-mediated spiroketal opening followed by an azide substitution and reduction sequence is employed to generate the spiroaminoketal motif of the natural product. Overall, this synthesis produced 5.2 g in a single pass in 15 total steps and 15.2% yield using a methodology that is atom economical, scalable, and requires no flash chromatography purifications.