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Synthesis
DOI: 10.1055/a-2779-1148
DOI: 10.1055/a-2779-1148
Paper
Published as part of the Special Issue dedicated to Dr. Dani Schultz, recipient of
the 2025 Dr. Margaret Faul Women in Chemistry Award
Asymmetric Synthesis of the 9-Azabicyclo[3.3.1]nonane Core of Macroline-Type Alkaloids
Authors
Supported by: National Institutes of Health
Funding Information We thank the National Institutes of Health for funding of our research program in this field. Work performed in the University of Pittsburgh X-ray Crystallography Facility (RRID:SCR_025125) and services and instruments used in this project were graciously supported, in part, by the University of Pittsburgh.
Dedication
Dedicated to Dr. Dani Schultz, the recipient of the 2025 Women in Chemistry Award.
Abstract
The signature indole-fused 9-azabicyclo[3.3.1]nonane (9-ABN) core of macroline-type alkaloids in its natural configuration has been accessed in 4 steps and 16% overall yield from 1H-indole and an l-menthyl nicotinate-derived pyridyl alcohol. The two starting fragments were condensed using a hydrogen auto-transfer (HA) strategy. The key stereocenter at C-5 was installed in up to 95:5 dr with a double diastereoselective, chiral auxiliary-assisted asymmetric transfer hydrogenation (CAATHy). This selective partial reduction of the pyridine to the tetrahydropyridine set the stage for stereospecific formation of the bridged, bicyclic 9-ABN system via a novel superacid-mediated cycloisomerization reaction. Starting from indole and 6-(hydroxymethyl)nicotinate esters, this new strategy provides rapid, protecting group- and transition metal-free access to the tetracyclic macroline core.
Keywords
Macroline - Alkaloids - 9-Azabicyclo[3.3.1]nonane - Hydrogen auto-transfer - Asymmetric transfer hydrogenation - Partial pyridine reductionPublication History
Received: 19 October 2025
Accepted after revision: 24 December 2025
Accepted Manuscript online:
25 December 2025
Article published online:
15 January 2026
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