Total Synthesis of Talatisamine

Zhou R., Dai G., Zhou X., Zhang M., Wu P., Zhang D., Song H., Liu X., Qin Y.

We reported the first successful preparation of fully functionalized aconitine AE fragment and attempts to access the pentacyclic skeleton of aconitine via radical cascade.

Liu J., Ma D.

A tetracyclic dinitrile was synthesized in twelve steps from cyclohex-2-en-1-one by using a chelation-triggered conjugate addition to a γ-hydroxy-substituted α,β-unsaturated nitrile and an oxidative dearomatization/Diels-Alder cycloaddition cascade as the key steps. The first total synthesis of azitine (in 17 steps) was achieved through a simple reductive cyclization of this intermediate and subsequent transformations while the total synthesis of the proposed structure of navirine C (in 19 steps) was accomplished by a hydrogen-atom-transfer reaction of the tetracyclic dinitrile, Pd/C-catalyzed reductive cyclization, and subsequent functional group manipulation.

Liu J., Ma D.

Nishiyama Y., Yokoshima S., Fukuyama T.

A synthesis of cardiopetaline has been accomplished via a Wagner-Meerwein rearrangement of a diol having the denudatine skeleton. The Wagner-Meerwein rearrangement could be facilitated simply by heating the diol with p-toluenesulfonic acid in pivalic acid, without preactivating the pivotal hydroxy group. This strategy does not require differentiation of several hydroxy groups in the substrate for the Wagner-Meerwein rearrangement and could be applied to the synthesis of more highly oxygenated aconitine-type diterpenoid alkaloids.

Kou K.G., Kulyk S., Marth C.J., Lee J.C., Doering N.A., Li B.X., Gallego G.M., Lebold T.P., Sarpong R.

The secondary metabolites that comprise the diterpenoid alkaloids are categorized into C18, C19, and C20 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 C18 (weisaconitine D), one C19 (liljestrandinine), and three C20 (cochlearenine, paniculamine, and N-ethyl-1α-hydroxy-17-veratroyldictyzine) natural products from a common intermediate.

Liu X., Qin Y.

Recent accomplishments in the total syntheses of diterpenoid alkaloids and their biosynthetically associated diterpenes have highly relied on an oxidative dearomatization/Diels–Alder cycloaddition strategy, and are highlighted in this article.

Minagawa K., Urabe D., Inoue M.

C19-diterpene alkaloids are a class of alkaloids with pharmacologically important activities having an intricately fused hexacyclic ABCDEF-ring system. Here we report expeditious assembly of the ACE-ring substructure 4a by applying a three-component coupling strategy. A radical–polar crossover reaction between an AE-ring radical precursor, a C-ring radical acceptor and an aldehyde was realized by the actions of Et3B and O2, resulting in the installation of three new stereocenters and extension of the carbon chain corresponding to the B-ring. As the ACE-ring 4a possesses the correct C4,11-quaternary and C10-tertiary carbons, 4a would serve as an advanced intermediate for constructing the entire C19-diterpene alkaloid structures.

Zhang X., Tu Y., Zhang F., Chen Z., Wang S.

1,2-Carbon atom rearrangement has been broadly applied as a guiding strategy in complex molecule assembly. As it entails the carbon-carbon or carbon-heteroatom bond migration between two vicinal atoms, this type of reaction is capable of generating structural complexity through a molecular skeletal reorganization. This review will focus on recent employment of this strategy in the total synthesis of natural products, highlighting the exceptional utility of such synthetic methodologies in the construction of intricate carbocycles, heterocycles or structurally complex motifs from synthetically more accessible precursors.

Subba Reddy B.V., Nair P.N., Antony A., Lalli C., Grée R.

The classical Prins cyclization reaction has been one of the most studied reactions during the last two decades and it has found many applications in key steps of natural product syntheses, especially for products containing pyran units and related structures in their core skeletons. The nitrogen-based version of the Prins reaction, aza-Prins cyclization, has found its own relevance in organic synthesis owing to the fact that it gives direct access to piperidines, which are even more widespread in natural products and in drugs. Even though the potential scope of the reaction is vast, and despite it having afforded significant progress in the synthesis of various azaheterocycles, its applications in the field of natural product synthesis is massively underdeveloped in comparison with the classical Prins reaction. A compilation of the applications of aza-Prins cyclization in the preparation of natural products and selected analogues, especially compounds of potential biological interest, is presented, with emphasis placed on the key roles of this reaction in the total synthesis of these products.

Li X., Zhu M., Wang Z., Liu X., Song H., Zhang D., Wang F., Qin Y.

A unified approach to four different (atisine, ajaconine, denudatine, and hetidine) diterpenoid alkaloid skeletons was developed and applied to the total synthesis of the natural products dihydroajaconine (2, atisine type) and gymnandine (4, denudatine type). The synthesis features a biogenetically inspired strategy that relies on C-H oxidation, aza-pinacol coupling, and aza-Prins cyclization as key steps.

Li X., Zhu M., Wang Z., Liu X., Song H., Zhang D., Wang F., Qin Y.

Kou K.G., Li B.X., Lee J.C., Gallego G.M., Lebold T.P., DiPasquale A.G., Sarpong R.

The denudatine-type diterpenoid alkaloids cochlearenine, N-ethyl-1α-hydroxy-17-veratroyldictyzine, and paniculamine have been synthesized for the first time (25, 26, and 26 steps from 16, respectively). These syntheses take advantage of a common intermediate (8) that we have previously employed in preparing aconitine-type natural products. The syntheses reported herein complete the realization of a unified strategy for the preparation of C20, C19, and C18 diterpenoid alkaloids.

Tabuchi T., Urabe D., Inoue M.

The fused 6/7/5/6/6-membered (ABCDE) ring system of talatisamine was synthesized in 22 steps. After preparation of the AE-ring structure from 2-(ethoxycarbonyl)cyclohexanone, elaboration of the carboskeleton was realized by sequential additions of allyl magnesium bromide and the lithiated C-ring. The C11-bridgehead radical derived from the ACE-ring underwent the 7-endo cyclization with the enone moiety to form the B-ring in C10-stereoselective and C11-stereospecific manners. The 6-endo cyclization of the remaining D-ring was in turn attained by using the silyl enol ether as the nucleophile and the PhSeCl-activated olefin as the electrophile. These radical and cationic cyclizations were demonstrated to be highly chemoselective, and they significantly contributed to streamlining the route to the intricately fused pentacycle of talatisamine.

Nishiyama Y., Yokoshima S., Fukuyama T.

The total synthesis of (-)-cardiopetaline, an aconitine-type natural product, has been accomplished. Our synthesis involved a Wagner-Meerwein rearrangement of a sulfonyloxirane that enabled, in a single step, the construction of the bicyclo[3.2.1] system in the aconitine skeleton and effective introduction of oxygen functional groups at the appropriate positions.

Hagiwara K., Tabuchi T., Urabe D., Inoue M.

The unique hexacyclic ring system of puberuline C was efficiently synthesized utilizing a radical-based cyclization/translocation/cyclization process and Mukaiyama aldol reaction.

Wang Y., Qi X.

Comprehensive SummaryNatural products with high oxidation states and complex chemical skeletons exhibit diverse bioactivities due to their unique interactions with biological targets. The high oxidation state is characterized by the presence of multiple oxygen‐containing functional groups such as hydroxyl groups, carbonyl groups, and epoxides that are usually tough to construct selectively. In recent years, thanks to the development of efficient strategies and sophisticated methodologies, significant advancements have been made in the total syntheses of highly oxidized natural products (HONPs). In this review, we highlight recent examples of HONPs focusing on tetrodotoxin (TTX) and its derivatives, steroidal alkaloids, sesquiterpenes, and diterpenoids since 2019. Key ScientistsIn 2005, the Yang group applied the thioureas as ligands in the Pauson−Khand reaction for total synthesis of triterpene natural products. The methodological advances have achieved total syntheses of a series of topologically complex natural products with diverse structural features in the following years. In 2009, the Baran group established a pioneering “two‐phase” approach for the total synthesis of highly oxidized terpenes, an innovative strategy has since inspired numerous advancements in the field. In 2011, Xu and Theodorakis achieved the total synthesis of (−)‐jiadifenolide, a highly oxidized sesquiterpene from Illicium. In 2012, the Li group applied 6π electrocyclization for total synthesis of natural products containing aromatic rings. In 2014, the Inoue group introduced the α‐alkoxy bridgehead radical, facilitating a unified total synthesis of ryanodane diterpenoids. In subsequent years, radical‐based convergent strategies were employed for assembling HONPs. The Li group developed the type ΙΙ [5+2] reaction, which can be efficiently applied in the total synthesis of HONPs featuring bridged ring systems. The Reisman group presented the oxidation pattern analysis that guided their synthetic designs for the synthesis of complex, highly oxidized ryanodane and isoryanodane diterpenes. In 2017, the Gao group reported a photoenolization/Diels‐Alder (PEDA) reaction for constructing related polycyclic rings with elevated oxidation states. In 2018, the Ding group developed an unprecedented oxidative dearomatization‐induced (ODI) [5+2] cycloaddition/pinacol‐ type 1,2‐acyl migration cascade to assemble the highly oxygenated bicyclo[3.2.1]octane ring system, which was subsequently applied to the synthesis of highly oxidized grayanane diterpenoids. In the same year, the Gui group explored “bioinspired” strategic transformations that enabled the rapid construction of core framework of steroid and terpenoid natural products. In 2020, the Luo group successfully synthesized several HONPs, including (−)‐batrachotoxinin, (−)‐zygadenine, and grayanane diterpenoids, employing elegant strategies. In 2021, the Zhang group developed site‐specific photochemical desaturation and late‐stage skeletal reorganization strategies, enabling the divergent total synthesis of Illicium sesquiterpenes. In 2022, the Jia group achieved the first total synthesis of (−)‐principinol C, subsequently accomplished six highly oxidized grayanane diterpenoids. More recently, the Trauner group reported a concise synthesis of tetrodotoxin, employing a particularly elegant strategy.

Yu F., Xu L.

A Pd-catalyzed transannular alkenylation synthetic strategy for construction of the BCDF tetracyclic ring system of biologically active aconitine-type C19-diterpenoid alkaloids was successfully developed.

Pocock I.A., Doulcet J., Rice C.R., Sweeney J.B., Gill D.M.

All five oxygen substituents and all six skeletal carbon atoms of the aconitine D ring are derived from d-glucose in a fully stereocontrolled synthesis featuring an enelactone to diketone rearrangement.

Yang Z., Rao H., Yin Y., Mu S., Jia Z., Ding H.

Wang Y., Gui J.

Morrow A.P., Smith M.W.

Asai H., Hagiwara K., Inoue M.

Talatisamine [(–)-1] is a C19-diterpenoid alkaloid with an intricately fused ABCDEF-ring system. In 2020, we reported a total synthesis of racemic talatisamine [(±)-1], in which AE-ring fragment (±)-5-α/5-β was utilized as the pivotal early-stage intermediate. Herein, we disclose the development of an enantioselective route to (–)-5-β for the total synthesis of (–)-1. Enantioselective intermolecular Mannich, Lewis acid-mediated intramolecular Mannich, and reductive N-ethylation reactions were employed as the three key transformations.

Wang H., Li Z., Dai R., Jiao N., Song S.

A mild and practical method for synthesizing sulfonyl derivatives, which have a wide range of applications in pharmaceuticals, materials, and organic synthesis, was described through the oxidative functionalization of thiols with DMSO/HBr.

Mizuno K., Nishiyama Y., Yokoshima S.

The ABCD ring system of C18/C19 diterpene alkaloids was constructed via cationic [5 + 2] cycloaddition and an intramolecular aldol reaction.

Chen J., Hou W., Ji J., Liu X., Qin Y.

The C19-diterpenoid alkaloids belong to a class of natural products with significant biological activities. These molecules are structurally characterized by complex cage-like skeletons and dense functional substituents. The efficient preparation of the A/E aza-bridged ring system, which is ubiquitous in C19-diterpenoid alkaloids, would lay an important foundation for their total synthesis. This paper reports a new asymmetric synthesis of the functionalized A/E bicyclic fragment of the C19-diterpenoid alkaloids, featuring desymmetrization, diastereoselective allylaltion, aldol hydroxymethylation, and reductive amination as key steps.

Ji J., Chen J., Qin S., Li W., Zhao J., Li G., Song H., Liu X., Qin Y.

Guo T., Peng F., Song X., Lei J., Yu F., Chu H., Yang K., Xu L.

A highly functionalized BCDE model ring system of aconitine has been synthesized for the first time via a strategy involving oxidative dearomatization/IMDA, Wagner–Meerwein rearrangement, Michael addition and reductive cyclization.

Shimakawa T., Nakamura S., Asai H., Hagiwara K., Inoue M.

Qasem A.M., Rowan M.G., Blagbrough I.S.

There are famous examples of simple (e.g., hemlock, Conium maculatum L.) and complex (e.g., opium poppy, Papaver somniferum L., Papaveraceae) piperidine-alkaloid-containing plants. Many of these are highly poisonous, whilst pepper is well-known gastronomically, and several substituted piperidine alkaloids are therapeutically beneficial as a function of dose and mode of action. This review covers the taxonomy of the genera Aconitum, Delphinium, and the controversial Consolida. As part of studying the biodiversity of norditerpenoid alkaloids (NDAS), the majority of which possess an N-ethyl group, we also quantified the fragment occurrence count in the SciFinder database for NDA skeletons. The wide range of NDA biodiversity is also captured in a review of over 100 recently reported isolated alkaloids. Ring A substitution at position 1 is important to determine the NDA skeleton conformation. In this overview of naturally occurring highly oxygenated NDAs from traditional Aconitum and Delphinium plants, consideration is given to functional effect and to real functional evidence. Their high potential biological activity makes them useful candidate molecules for further investigation as lead compounds in the development of selective drugs.

Truax N.J., Ayinde S., Liu J.O., Romo D.

A pharmacophore-directed retrosynthetic strategy was applied to the first total synthesis of the cembranoid rameswaralide in order to simultaneously achieve a total synthesis while also developing a structure-activity relationship profile throughout the synthetic effort. The synthesis utilized a Diels-Alder lactonization process, including a rare kinetic resolution to demonstrate the potential of this strategy for an enantioselective synthesis providing both the 5,5,6- and, through a ring expansion, 5,5,7-tricyclic ring systems present in several Sinularia soft coral cembranoids. A pivotal synthetic intermediate, a tricyclic epoxy α-bromo cycloheptenone, displayed high cytotoxicity with interesting selectivity toward the HCT-116 colon cancer cell line. This intermediate enabled the pursuit of three unique D-ring annulation strategies including a photocatalyzed intramolecular Giese-type radical cyclization and a diastereoselective, intramolecular enamine-mediated Michael addition, with the latter annulation constructing the final D-ring to deliver rameswaralide. The serendipitous discovery of an oxidation state transposition of the tricyclic epoxy cycloheptenone proceeding through a presumed doubly vinylogous, E1-type elimination enabled the facile introduction of the required α-methylene butyrolactone. Preliminary biological tests of rameswaralide and precursors demonstrated weak cytotoxicity; however, the comparable cytotoxicity of a simple 6,7-bicyclic β-keto ester, corresponding to the CD-ring system of rameswaralide, to that of the natural product itself suggests that such bicyclic β-ketoesters may constitute an interesting pharmacophore that warrants further exploration.