1. Academic Validation
  2. Total Syntheses of Echitamine, Akuammiline, Rhazicine, and Pseudoakuammigine

Total Syntheses of Echitamine, Akuammiline, Rhazicine, and Pseudoakuammigine

  • Angew Chem Int Ed Engl. 2019 Apr 23;58(18):6053-6058. doi: 10.1002/anie.201901086.
Xiang Zhang 1 Badrinath N Kakde 1 Rui Guo 1 Sonyabapu Yadav 1 Yucheng Gu 2 Ang Li 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China.
  • 2 Syngenta, Jealott's Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, UK.
Abstract

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).

Keywords

Meisenheimer rearrangement; Polonovski-Potier reaction; cascade reactions; indole alkaloids; total synthesis.

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