A Unifying Synthesis Approach to the C₁₈-, C₁₉-, and C₂₀-Diterpenoid Alkaloids

Abstract

The secondary metabolites that comprise the diterpenoid alkaloids are categorized into C, C, and C families depending on the number of contiguous carbon atoms that constitute their central framework. Herein, we detail our efforts to prepare these molecules by chemical synthesis, including a photochemical approach, and ultimately a bioinspired strategy that has resulted in the development of a unifying synthesis of one C (weisaconitine D), one C (liljestrandinine), and three C (cochlearenine, paniculamine, and N-ethyl-1α-hydroxy-17-veratroyldictyzine) natural products from a common intermediate.

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

“…Depictions B1 and B2 are widely employed by organic synthetic chemists for various reasons, e.g. B-ring with the largest number of bridgeheads displayed in the front may benet retrosynthetic analysis, 44,45 and it is also useful for designing disconnections of C-, D-and F-rings as these drawings correctly express the conformations. 46,47 A rotated depiction of B2 (depiction B3, Fig.…”

Retrosynthetic strategies and their impact on synthesis of arcutane natural products

“…The value of such rearrangements is difficult to dene; however, they can provide the ability to trace back a complex bridged framework to a more readily accessible one and have been used in other diterpenoid alkaloid syntheses. 18,[41][42][43][44][45] In the case of the Li synthesis of the arcutanetype alkaloids, the bioinspired rearrangement is central to what is the shortest reported syntheses to date. That said, bioinspired syntheses and retrosyntheses borne out of bond-network analysis are not necessarily mutually exclusive; Li's rearrangement forges the maximally bridged ring at a late stage and all other disconnections follow the tenets of bond-network analysis.…”

Total Synthesis of Talatisamine

“…[6,7] These strategies led to creative solutions enabling the total syntheses of seven C 18and C 19 -diterpenoid alkaloids with various numbers of oxygen functionalities (Figure 1). These include the syntheses of 1 (5 oxygen functionalities,4 3s teps,l ongest linear sequence), chasmanine (6 oxygen functionalities,5 6s teps), and 13desoxydelphonine (6 oxygen functionalities,5 7s teps) by the Wiesner group in the 1970s, [8] neofinaconitine (5 oxygen functionalities,3 4s teps) by the Gin group in 2013, [9] weisaconitine D( 4o xygen functionalities,3 3s teps) and liljestrandinine (4 oxygen functionalities,3 1s teps) by the Sarpong group in 2015, [10] and cardiopetaline (3 oxygen functionalities,3 3o r2 7s teps) by the Fukuyama group in 2016. [11] These total syntheses over the years represent the state of the art of organic synthesis.H erein, we describe the development of an efficient strategy for assembling the entire hexacycle of C 18 -a nd C 19 -diterpenoid alkaloids from two structurally simple fragments,a nd the achievement of as econd total synthesis of talatisamine (1)i n3 3s teps from 2cyclohexenone (8).…”