Synthesis of Three-Dimensionally Fascinating Diterpenoid Alkaloids and Related Diterpenes

Abstract

Conspectus Three-dimensional cage-like natural products represent astounding and long-term challenges in the research endeavors of total synthesis. A central issue that synthetic chemists need to address lies in how to efficiently construct the polycyclic frameworks as well as to install the requisite substituent groups. The diterpenoid alkaloids that biogenetically originate from amination of diterpenes and diversify through late-stage skeletal reorganization belong to such a natural product category. As the characteristic components of the Aconitum and Delphinium species, these molecules display a rich array of biological activities, some of which are used as clinical drugs. More strikingly, their intricate and beautiful architectures have rendered the diterpenoid alkaloids elusive targets in the synthetic community. The successful preparation of these intriguing compounds relies on the development of innovative synthetic strategies. Our laboratory has explored the total synthesis of a variety of diterpenoid alkaloids and their biogenetically related diterpenes over the past decade. In doing so, we have accessed 6 different types of skeletons (atisine-, denudatine-, arcutane-, arcutine-, napelline-, and hetidine-type) and achieved the total synthesis of 6 natural products (isoazitine, dihydroajaconine, gymnandine, atropurpuran, arcutinine, and liangshanone). Strategically, an oxidative dearomatization/Diels–Alder (OD/DA) cycloaddition sequence was widely employed in our synthesis to form the ubiquitous [2.2.2]-bicyclic ring unit and its related ring-distorted derivatives in these complex target molecules. This protocol, in combination with additional bond-forming key steps, allowed us to prepare the corresponding polycyclic alkaloids and a biogenetically associated diterpene. For example, bioinspired C–H activation, aza-pinacol, and aza-Prins cyclizations were used toward a unified approach to the atisine-, denudatine-, and hetidine-type alkaloids via ajaconine intermediates in our first work. To pursue the synthesis of atropurpuran and related arcutine alkaloids, we harnessed a ketyl-olefin radical cyclization to assemble the carbocycle and an aza-Wacker cyclization to construct the unusual pyrrolidine ring. Furthermore, a one-pot alkene cleavage/Mannich cyclization tactic, sequential Robinson annulation, and intramolecular aldol addition were developed, which facilitated the formation of the napelline alkaloid scaffold and the first total synthesis of liangshanone. Finally, the utility of the Mannich cyclization and enyne cycloisomerization reactions allowed for access to the highly functionalized A/E and C/D ring fragments of aconitine (regarded as the “Holy Grail” of diterpenoid alkaloids). This Account provides insight into our synthetic designs and approaches used toward the synthesis of diterpenoid alkaloids and relevant diterpenes. These endeavors lay a foundation for uncovering the biological profiles of associated molecules and also serve as a reference for preparing other three-dimensionally fascinat...

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

“…Disassembly of the bicyclo[2.2.2]­octane motif in talassimidine and talassamine led back to 23 . Instead of the commonly used Diels–Alder cycloaddition strategy, formation of the C12–C13 bond of 23 would give the bicyclo[2.2.2]­octane motif and establish the hetidine core. Inspired by our previous success in constructing the B ring of hetisine through a dearomative free radical addition, we posited that addition of a ketyl radical to the arene moiety would yield the B ring and concurrently install a hydroxyl group.…”

“…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 .…”

“…The limited success in the synthesis of hetidine-type alkaloids can be attributed to the synthetic challenge associated with the rigid hexacyclic cage-shaped skeleton and more problematically, the different oxygen substitutions at various positions of the core frameworks. ,, To develop new synthetic strategies to access diterpenoid alkaloids with complex oxygen substitution patterns, we embarked on a synthetic program toward the synthesis of talassimidine ( 4 ) and talassamine ( 5 ), two hetidine-type alkaloids initially isolated from Aconitum talassicum M. Pop. by Nishanov and then reisolated from Delphinium campylocentrum Maxim.…”

Divergent Total Syntheses of Napelline-Type C20-Diterpenoid Alkaloids: (−)-Napelline, (+)-Dehydronapelline, (−)-Songorine, (−)-Songoramine, (−)-Acoapetaldine D, and (−)-Liangshanone

“…The similar strained cage skeleton also exists in various ent -atisane diterpene-derived alkaloids. These intriguing structural features rendered these C 20 -diterpenoid alkaloids challenging and attractive targets for synthetic chemists . During the past decades, remarkable achievements have been accomplished toward accessing ent -atisane diterpene-derived alkaloids such as atisines, hetidines, hetisines, denudatines, and arcutines .…”

Mechanism of the Fe(iii)-catalyzed synthesis of hexahydropyrimidine with α-phenylstyrene: a DFT study

“…23 Although the above studies on the synthesis of HHPs have their own merits, they mainly focus on the reaction of C]O bonds and primary amines. In 2017, Cui et al investigated the acid-catalyzed [2 + 2 + 2] system for HHPs, which overcame the challenge of insufficient nucleophilicity of the iminium species using the intermolecular aza-Prins reaction [24][25][26][27] and directly synthesizing the target product from the alkene precursor. 28 On the basis of this mechanism detection experiment, Fang et al calculated the possible reaction mechanisms, catalytic species, and regioselectivity in the cycloaddition reaction for this system using density functional theory.…”