Total Synthesis of Metaphanine and Oxoepistephamiersine

• Published in: Angewandte Chemie International Edition Vol. 62; no. 40; pp. e202310917 - n/a
• Main Authors: Sun, Ya‐Kui, Qiao, Jin‐Bao, Xin, Yu‐Meng, Zhou, Qin, Ma, Zhi‐Hua, Shao, Hui, Zhao, Yu‐Ming
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 02.10.2023; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Alkylation; Asymmetric synthesis; Cascade Annulation; Chemical reactions; Chemical synthesis; Chemistry; Chemistry, Multidisciplinary; Enantiomers; Hasubanan Alkaloids; Hydrogen bonds; Late-Stage Oxidation; Oxidation; Palladium; Palladium Catalysis; Physical Sciences; Science & Technology; Stereoselectivity; Total Synthesis; Total Synthesis; CHEMOSELECTIVE REDUCTION; ROUTES; ENANTIOSELECTIVE TOTAL SYNTHESES; SECONDARY; Cascade Annulation; Late-Stage Oxidation; Palladium Catalysis; Hasubanan Alkaloids; DIRECTED HYDROBORATION; PROTONATION; AMIDES
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202310917

Herein, we report a concise and divergent synthesis of the complex hasubanan alkaloids metaphanine and oxoepistephamiersine from commercially available and inexpensive cyclohexanedione monoethylene acetal. Our synthesis features a palladium‐catalyzed cascade cyclization reaction to set the tricyclic carbon framework of the desired molecules, a regioselective Baeyer–Villiger oxidation followed by a MeNH2 triggered skeletal reorganization cascade to construct the benzannulated aza[4.4.3]propellane, and a strategically late‐stage regio‐/diastereoselective oxidative annulation of sp3 C−H bond to form the challenging THF ring system and hemiketal moiety in a single step. In addition, a highly enantioselective alkylation of cyclohexanedione monoethylene acetal paved the way for the asymmetric synthesis of target molecular. Two complex hasubanan alkaloids were synthesized from inexpensive cyclohexanedione monoethylene acetal by a divergent route featuring a palladium‐catalyzed cascade cyclization. Regioselective Baeyer–Villiger oxidation followed by MeNH2‐triggered skeletal reorganization formed the benzannulated aza[4.4.3]propellane, and late‐stage regio‐ and diastereoselective oxidative annulation of a sp3 C−H bond formed the challenging tetrahydrofuran ring system.