Total Syntheses of Echitamine, Akuammiline, Rhazicine, and Pseudoakuammigine

Echitamine (1) and akuammiline (2) are representative members of a fascinating class of monoterpenoid indole alkaloids. We report the syntheses of 2 and its congener deacetylakuammiline (3). The azabicyclo[3.3.1]nonane motif was assembled through silver-catalyzed internal alkyne cyclization, and one-pot C-O bond cleavage/C-N bond formation furnished the pentacyclic scaffold. Compound 3 then served as a common intermediate for preparing a series of structurally diverse and synthetically challenging congeners including 1. A position-selective Polonovski-Potier reaction followed by formal N-4 migration built the core of N-demethylechitamine (4) and 1. An alternative route featuring Meisenheimer rearrangement gave 4 as well. Oxidation of the alcohol within 3 gave rhazimal (5), which underwent tandem indolenine hydrolysis, hemiaminalization, and hemiketalization to form rhazicine (6). A sequence of N,O-ketalization and reductive amination secured the chemoselectivity of N-methylation, leading to pseudoakuammigine (7).