First total synthesis of ent-gelsedine via a novel iodide-promoted allene N-acyliminium ion cyclization.
The first total synthesis of the oxindole alkaloid gelsedine (1) starting from (S)-malic acid is described. The key step is a novel iodide-promoted intramolecular reaction of an allene with an N-acyliminium ion intermediate which provided in a single step the bicyclic vinyl iodide 11. Other important steps are the highly stereoselective Pd-catalyzed Heck cyclization of N-methylanilide 23a which led to the desired spiro-oxindole 24a, the fully regioselective intramolecular oxymercuration of 25a to the desired cyclic ether, and the remarkable oxindole N-demethylation of 29 via a radical mechanism by using dibenzoyl peroxide. The total synthesis was concluded by the stereoselective introduction of the ethyl group from the bis-Boc compound 41 followed by methoxylation of the oxindole nitrogen. This total synthesis leads to the unnatural (+)-enantiomer of gelsedine in 21 steps and 0.10% overall yield.
Beyersbergen van Henegouwen
W G
WG
Laboratory of Organic Chemistry, Institute of Molecular Chemistry, University of Amsterdam, Nieuwe Achtergracht 129, 1018 WS Amsterdam, The Netherlands.
Fieseler
R M
RM
Rutjes
F P
FP
Hiemstra
H
H
D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry; D018360:Crystallography, X-Ray; D003500:Cyclization; D009682:Magnetic Resonance Spectroscopy; D000078183:Oxindoles; D010944:Plants / Q000737:chemistry*; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013237:Stereoisomerism
D000470:Alkaloids; D000078183:Oxindoles; C418735:gelsedine