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Stereoselective and Stereospecific Triflate‐Mediated Intramolecular Schmidt Reaction: Ready Access to Alkaloid Skeletons **
Author(s) -
Gnägi Lars,
Arnold Remo,
Giornal Florence,
Jangra Harish,
Kapat Ajoy,
Nyfeler Erich,
Schärer Robin M.,
Zipse Hendrik,
Renaud Philippe
Publication year - 2021
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202016892
Subject(s) - chemistry , iminium , stereoselectivity , intramolecular force , stereospecificity , trifluoromethanesulfonate , schmidt reaction , stereochemistry , azepine , racemization , diastereomer , azide , moiety , medicinal chemistry , organic chemistry , catalysis
The stereoselectivity and stereospecificity of the triflate‐mediated intramolecular Schmidt reaction of substituted 3‐(1‐azidocyclohexyl)propanol derivatives leading to octahydro‐1H‐pyrrolo[1,2‐a]azepine, the structural skeleton of several important families of alkaloids such as the Stemona alkaloids, has been examined. The reaction involves an initial intramolecular S N 2 reaction between the azide moiety and the triflate affording an intermediate spirocyclic aminodiazonoium salt that undergoes the expected 1,2‐shift/N 2 ‐elimination followed by hydride‐mediated iminium salt reduction. Remarkably, chiral alcohols are converted to the azabicyclic derivative with no or limited racemization. The initial asymmetric alcohol center controls the diastereoselectivity of the whole process, leading to the formation of one out of the four possible diastereoisomers of disubstituted octahydro‐1H‐pyrrolo[1,2‐a]azepine. The origin of the stereoselectivity is rationalized based on theoretical calculations. The concise synthesis of (−)‐(cis)‐3‐propylindolizidine and (−)‐(cis)‐3‐butyllehmizidine, two alkaloids found in the venom of workers of the ant Myrmicaria melanogaster, is reported.