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

Abstract

The first intramolecular aza‐Prins cyclization of aza‐Achmatowicz rearrangement products was developed with identification of bismuth tribromide (BiBr3) to play a dual role: efficient Lewis acid and source of bromide nucleophile. This work represents a novel and efficient approach for the facile construction of highly functionalized 9‐azabicyclo [3.3.1] nonanes (9‐ABNs), which are valuable synthetic building blocks and a powerful platform in the synthesis of a variety of alkaloid natural products or drug molecules. The substrate scope was investigated with 27 successful examples that employ 1,1‐disubstituted alkenes, 1,2‐disubstituted alkenes, alkynes, and allenes as diverse substrates for the aza‐Prins cyclization with good to excellent yields. Finally, we showcased the application of this new approach to the enantioselective total syntheses of six indole alkaloids: (−)‐suaveoline (1), (−)‐norsuaveoline (2), (−)‐macrophylline (3), (+)‐normacusine B (4), (+)‐Na‐methyl‐16‐epipericyclivine (5) and (+)‐affinisine (6) in total 9‐14 steps. This work significantly expands the synthetic utility of 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.

Total Synthesis of (–)-Rauvomine B via a Strain-Promoted Intramolecular Cyclopropanation

“…[9][10][11][12][13][14][15][16][17][18] Continued interest in the family has been showcased in a series of creative approaches developed in the past five years. [19][20][21][22][23][24][25][26] Despite this rich body of work, synthetic approaches capable of addressing the particular structural challenges presented by rauvomines A-C (1-3) are yet to be developed. While the Cook group has developed an approach to the less common C-19 methyl-bearing sarpagines, 16 synthetic solutions to the alkyl chloride or cyclopropane motifs have not been reported to date.…”