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.

Asymmetric Total Synthesis of Hetidine-Type C20-Diterpenoid Alkaloids: (+)-Talassimidine and (+)-Talassamine

“…Of the biosynthetically related atisine-, hetidine-, and hetisine-type C 20 -diterpenoid alkaloids, the hexacyclic hetidine core has a characteristic C14–C20 linkage; besides the C14–C20 linkage, the hetisine core has an additional C6–N linkage, forming a complex heptacyclic framework. The unique biological profiles and structural complexity of C 20 -diterpenoid alkaloids render them highly sought-after synthetic targets. − Successful total syntheses of hetisine-type alkaloids have been reported by the groups of Muratake/Natsume, Gin, and Sarpong, as well as our group, reflecting considerable achievements toward total synthesis of various C 20 -diterpenoid alkaloids in recent years. − However, there has been limited success in the synthesis of the seemingly less complex hetidine-type alkaloids, despite considerable efforts having been made toward this subtype. , Guided by network analysis, Sarpong’s group accomplished a unified total synthesis of C 18 -, C 19 -, and C 20 -diterpenoid alkaloids ,,, and developed an elegant approach of Ga-catalyzed cycloisomerization to synthesize dihydronavirine, a structurally very similar analogue of navirine. , Baran’s group applied a two-phase synthetic strategy to synthesize the atisine alkaloids and construct the hetidine skeleton from a readily available ent -kaurane . Qin and Liu developed an efficient biomimetic approach to access the denudatine- and atisine-type alkaloids and the hetidine skeleton from an atisine-type precursor .…”

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

“…Although the semipinacol rearrangement has been used in many total syntheses, 15 it is not typically employed as part of a fragment coupling strategy; we anticipated that this approach could highlight the utility of this overall two-step tactic for building polycyclic systems. Finally, epoxyketone 9 and alkenyl bromide 10 would be prepared from the simple starting materials cyclopent-2-en-1-one (11) and phenol (12), respectively. It was expected that this approach to (-)-1 would also provide access to (-)-( 2) and (-)-(3) through adjustments to the final sequence of reduction steps.…”

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

“…7 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 coworkers,8 and more recent contributions by the Sarpong, 9 Fukuyama, 10 and Inoue labs. 11 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, 12 as well as an elegant synthesis by Gin and coworkers of the C18 norditerpenoid alkaloid neofinaconitine (not shown).…”