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J Am Chem Soc. 2013 Sep 25;135(38):14313-20. doi: 10.1021/ja4064958. Epub 2013 Sep 16.

Total synthesis, relay synthesis, and structural confirmation of the C18-norditerpenoid alkaloid neofinaconitine.

Author information

1
Tri-Institutional PhD Program in Chemical Biology, ‡Molecular Pharmacology & Chemistry Program, and Tri-Institutional Research Program, Memorial Sloan-Kettering Cancer Center , 1275 York Avenue, Box 422, New York, New York 10065, United States.

Abstract

The first total synthesis of the C18-norditerpenoid aconitine alkaloid neofinaconitine and relay syntheses of neofinaconitine and 9-deoxylappaconitine from condelphine are reported. A modular, convergent synthetic approach involves initial Diels-Alder cycloaddition between two unstable components, cyclopropene 10 and cyclopentadiene 11. A second Diels-Alder reaction features the first use of an azepinone dienophile (8), with high diastereofacial selectivity achieved via rational design of siloxydiene component 36 with a sterically demanding bromine substituent. Subsequent Mannich-type N-acyliminium and radical cyclizations provide complete hexacyclic skeleton 33 of the aconitine alkaloids. Key endgame transformations include the installation of the C8-hydroxyl group via conjugate addition of water to a putative strained bridghead enone intermediate 45 and one-carbon oxidative truncation of the C4 side chain to afford racemic neofinaconitine. Complete structural confirmation was provided by a concise relay synthesis of (+)-neofinaconitine and (+)-9-deoxylappaconitine from condelphine, with X-ray crystallographic analysis of the former clarifying the NMR spectral discrepancy between neofinaconitine and delphicrispuline, which were previously assigned identical structures.

PMID:
24040959
PMCID:
PMC3883312
DOI:
10.1021/ja4064958
[Indexed for MEDLINE]
Free PMC Article

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