Total Synthesis of Talatisamine

Abstract

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 1α-hydroxy-A-rings of norditerpenoid alkaloids are twisted-boat conformers

“…Depiction A2 which is viewing depiction A1 from the other face (it is not the enantiomer) was also employed in order to present the D-, E-or F-ring on the b-face that might be benecial for retrosynthetic analysis. [39][40][41] Depictions B1 and B2 are also popularly used. 42,43 Generally, these depictions B1 and B2 allow almost all the rings to be shown in the correct conformation, with well-balanced bond lengths (not of extreme length), and reasonable orientations of substituted functional groups.…”

Structural Studies of Norditerpenoid Alkaloids: Conformation Analysis in Crystal and in Solution States

“…Polycyclic norditerpenoid alkaloids (C 19 -and C 18 -norditerpenoid alkaloids, NDAs), isolated from Aconitum and Delphinium, are attractive natural products for scientists working in chemistry, biology, and pharmacology. [1][2][3] Although these alkaloids all have the same parent skeleton (Figure 1), they display different pharmacological activities. Aconitine (1, a typical C 19 À NDA) maintains cardiac voltage-sensitive sodium channels (VSSCs) in an open-state inducing arrhythmia, [4] whereby it can be lethal depending upon dose.…”

“…Polycyclic norditerpenoid alkaloids (C 19 ‐ and C 18 ‐norditerpenoid alkaloids, NDAs), isolated from Aconitum and Delphinium , are attractive natural products for scientists working in chemistry, biology, and pharmacology [1–3] . Although these alkaloids all have the same parent skeleton (Figure 1), they display different pharmacological activities.…”

Total Syntheses of the C19 Diterpenoid Alkaloids (−)-Talatisamine, (−)-Liljestrandisine, and (−)-Liljestrandinine by a Fragment Coupling Approach

“… 9 The cationic rearrangements involved in the biosynthesis of these natural products have also played an important role in many of the total syntheses of the C19 DTAs, including the pioneering efforts in the 1970s by Wiesner and co-workers, 10 − 13 and more recent contributions by the Sarpong, 14 Fukuyama, 15 and Inoue laboratories. 16 In each of these approaches, the denudatine-type bicyclo[2.2.2]octane is first assembled by a Diels–Alder reaction, and then rearranged at a late stage to the aconitine-type skeleton. Beyond these bioinspired strategies, a number of other approaches to the C19 DTAs have been disclosed, 17 − 28 as well as an elegant synthesis by Gin and co-workers of the C18 norditerpenoid alkaloid neofinaconitine (not shown).…”