BiBr3‐Mediated Intramolecular Aza‐Prins Cyclization of Aza‐Achmatowicz Rearrangement Products: Asymmetric Total Synthesis of Suaveoline and Sarpagine Alkaloids

• Published in: Angewandte Chemie International Edition 2023-10, Vol.62 (44), p.e202311671-e202311671
• Main Authors: Wai Fung Cheng, Ma, Shiqiang, Yin Tung Lai, Yuen Tsz Cheung, Akkarasereenon, Kornkamon, Zhou, Yiqin, Tong, Rongbiao
• Format: Article
• Language: English
• Subjects: Alkaloids; Alkenes; Alkynes; Bismuth; Construction; Enantiomers; Lewis acid; Natural products; Nonanes; Nucleophiles; Substrates; Synthesis
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202311671

An intramolecular aza‐Prins cyclization of aza‐Achmatowicz rearrangement products was developed in which bismuth tribromide (BiBr3) plays a dual role as an efficient Lewis acid and source of the bromide nucleophile. This approach enables the facile construction of highly functionalized 9‐azabicyclo[3.3.1]nonanes (9‐ABNs), which are valuable synthetic building blocks and a powerful platform for the synthesis of a variety of alkaloid natural products and drug molecules. Suitable substrates for the aza‐Prins cyclization include 1,1‐disubstituted alkenes, 1,2‐disubstituted alkenes, alkynes, and allenes, with good to excellent yields observed. Finally, we showcase the application of this new approach to the enantioselective total synthesis of six indole alkaloids: (−)‐suaveoline (1), (−)‐norsuaveoline (2), (−)‐macrophylline (3), (+)‐normacusine B (4), (+)‐Na‐methyl‐16‐epipericyclivine (5) and (+)‐affinisine (6) in a total of 9–14 steps. This study significantly expands the synthetic utility of the aza‐Achmatowicz rearrangement, and the strategy (aza‐Achmatowicz/aza‐Prins) is expected to be applicable to the total synthesis of other members of the big family of macroline and sarpagine indole alkaloids.