Concise Asymmetric Syntheses of Streptazone A and Abikoviromycin

• Published in: Angewandte Chemie International Edition Vol. 60; no. 19; pp. 10521 - 10525
• Main Authors: Wørmer, Gustav J., Villadsen, Nikolaj L., Nørby, Peter, Poulsen, Thomas B.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 03-05-2021
• Edition: International ed. in English
• Subjects: asymmetric catalysis; Asymmetric synthesis; Asymmetry; Conjugation; electrophile; Enantiomers; Epoxidation; Iridium; Natural products; Rhodium; Target recognition; total synthesis; transition metal catalysis; electrophile; natural products; asymmetric catalysis; total synthesis; transition metal catalysis
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202101439

Streptazone A and abikoviromycin are alkaloids that both feature an unusual arrangement of reactive functionalities within a compact tricyclic ring system. Here, we report a highly concise asymmetric synthesis of both natural products. The route first constructs another family member, streptazone B1, using a rhodium‐catalyzed distal selective allene‐ynamide Pauson–Khand reaction. A regio‐ and enantioselective epoxidation under chiral phase‐transfer catalytic conditions directly afforded streptazone A in 8 steps overall. In one additional step, a chemoselective, iridium‐catalyzed reduction of the enaminone system then gave abikoviromycin. The reactivity of streptazone A towards a cysteine mimic, N‐acetylcysteamine, was studied and revealed unanticipated transformations, including bis‐thiol conjugation which may proceed via formation of a cyclopentadienone intermediate. With flexible access to these compounds, studies aimed to identify their direct biological targets are now possible.
A concise route to deliver [4.3.0] alkaloid natural products featuring an allene‐ ynamide Pauson–Khand cyclization, an asymmetric and highly regioselective epoxidation and a chemoselective iridium‐catalyzed reduction is presented. The route delivers streptazone B1, streptazone A and abikoviromycin for the first time, and lastly demonstrates an idiosyncratic thiol reactivity characteristic for streptazone A.