Total Synthesis of Talatisamine

Talatisamine (1) is a member of the C19‐diterpenoid alkaloid family, and exhibits K+ channel inhibitory and antiarrhythmic activities. The formidable synthetic challenge that 1 presents is due to its highly oxidized and intricately fused hexacyclic 6/7/5/6/6/5‐membered‐ring structure (ABCDEF‐ring) w...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2020-01, Vol.59 (1), p.479-486
Main Authors: Kamakura, Daiki, Todoroki, Hidenori, Urabe, Daisuke, Hagiwara, Koichi, Inoue, Masayuki
Format: Article
Language:English
Subjects:
Aconitine - analogs & derivatives
Aconitine - chemical synthesis
Aconitine - chemistry
Aconitum - chemistry
alkaloids
cyclization
Diterpenes
Forging
Humans
Mercury
Molecular Structure
Potassium channels
rearrangement
Ring structures
Synthesis
terpenoids
total synthesis
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Summary:Talatisamine (1) is a member of the C19‐diterpenoid alkaloid family, and exhibits K+ channel inhibitory and antiarrhythmic activities. The formidable synthetic challenge that 1 presents is due to its highly oxidized and intricately fused hexacyclic 6/7/5/6/6/5‐membered‐ring structure (ABCDEF‐ring) with 12 contiguous stereocenters. Here we report an efficient synthetic route to 1 by the assembly of two structurally simple fragments, chiral 6/6‐membered AE‐ring 7 and aromatic 6‐membered D‐ring 6. AE‐ring 7 was constructed from 2‐cyclohexenone (8) through fusing an N‐ethylpiperidine ring by a double Mannich reaction. After coupling 6 with 7, an oxidative dearomatization/Diels–Alder reaction sequence generated fused pentacycle 4 b. The newly formed 6/6‐membered ring system was then stereospecifically reorganized into the 7/5‐membered BC‐ring of 3 via a Wagner–Meerwein rearrangement. Finally, Hg(OAc)2 induced an oxidative aza‐Prins cyclization of 2, thereby forging the remaining 5‐membered F‐ring. The total synthesis of 1 was thus accomplished by optimizing and orchestrating 33 transformations from 8. The highly oxidized and intricately fused hexacyclic structure (ABCDEF‐ring) of talatisamine with 12 contiguous stereocenters presents a formidable challenge for chemical construction. An efficient strategy, in which the entire hexacycle is assembled from a chiral AE‐ring fragment and an aromatic D‐ring, led to the total synthesis of talatisamine in 33 steps from 2‐cyclohexenone.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201912737