Total synthesis of dihydrolysergic acid and dihydrolysergol: development of a divergent synthetic strategy applicable to rapid assembly of D-ring analogs

The total syntheses of dihydrolysergic acid and dihydrolysergol are detailed based on a Pd(0)-catalyzed intramolecular Larock indole cyclization for the preparation of the embedded tricyclic indole (ABC ring system) and a subsequent powerful inverse electron demand Diels–Alder reaction of 5-carbomet...

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Bibliographic Details
Published in:Tetrahedron 2015-09, Vol.71 (35), p.5897-5905
Main Authors: Lee, Kiyoun, Poudel, Yam B., Glinkerman, Christopher M., Boger, Dale L.
Format: Article
Language:English
Subjects:
1,2,3-Triazine cycloaddition
Diels–Alder cycloaddition
Ergot alkaloids
Palladium catalyzed indole synthesis
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Summary:The total syntheses of dihydrolysergic acid and dihydrolysergol are detailed based on a Pd(0)-catalyzed intramolecular Larock indole cyclization for the preparation of the embedded tricyclic indole (ABC ring system) and a subsequent powerful inverse electron demand Diels–Alder reaction of 5-carbomethoxy-1,2,3-triazine with a ketone-derived enamine for the introduction of a functionalized pyridine, serving as the precursor for a remarkably diastereoselective reduction to the N-methylpiperidine D-ring. By design, the use of the same ketone-derived enamine and a set of related complementary heterocyclic azadiene [4+2] cycloaddition reactions permitted the late stage divergent preparation of a series of alternative heterocyclic derivatives not readily accessible by more conventional approaches. [Display omitted]
ISSN:0040-4020
1464-5416
DOI:10.1016/j.tet.2015.05.093