The structures of talatisamine and cammaconine by correlation with isotalatizidine

Pelletier S.W., Keith L.H., Parthasarathy P.C.

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.

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.

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

Delayre B., Wang Q., Zhu J.

The art of natural product total synthesis is closely associated with two major determinants: the development/application of novel chemical reactions and the innovation in strategic use of classic organic reactions. While purposely seeking/applying a new synthetic methodology allowing nonconventional bond disconnections could shorten the synthetic route, the development of domino processes composed of a series of well-established reactions could also lead to a concise, practical, and aesthetically appealing synthesis. As an important class of textbook reactions, the 1,2-anionotropic rearrangements discovered at the dawn of modern organic chemistry have important bearings not only on chemical synthesis but also on the conceptual breakthroughs in the field. In its basic form, the 1,2-shift affords nothing but a constitutional isomer of the starting material and is therefore not a complexity-generating transformation. However, such a simple 1,2-shift could in fact change the molecular topology if the precursor is cleverly designed. More dramatically, it can metamorphosize the structure of the substrate when it is combined with other transformations in a domino sequence. In this Outlook, we highlight recent examples of natural product synthesis featuring a key domino process incorporating a 1,2-anionotropic rearrangement. Specifically, domino reactions integrating Wagner-Meerwein, pinacol, α-ketol, α-aminoketone, α-iminol, or benzilic acid rearrangements will be discussed.

Shimakawa T., Hagiwara K., Inoue M.

Abstract Talatisamine (1) is a highly oxygenated C19-diterpenoid alkaloid with K+ channel inhibitory, antiarrhythmic, and neuroprotective activities. Its intricately fused 6/7/5/6/6/5-membered hexacyclic structure (ABCDEF-ring) possesses one nitrogen functionality, five oxygen functionalities, and 12 contiguously aligned stereocenters. This account describes the development of convergent strategies to efficiently assemble this synthetically challenging natural product. First, we explored two radical-based strategies. Treatment of the AE-ring with Et3B and O2 generated a highly reactive C11-bridgehead radical, which sequentially added to the C-ring and the aldehyde via a radical-polar crossover mechanism to afford ACE-ring substructure 6 in a single step. Alternatively, after coupling of the AE-ring and C-ring, the C11-bridgehead radical was utilized to cyclize the central 7-membered B-ring. The 6-membered D-ring was then forged by selenium-induced 6-endo cyclization to furnish ABCDE-ring 3. Second, we pursued a skeletal rearrangement strategy, which culminated in the total synthesis of 1. The D-ring was coupled with the AE-ring as the aromatic ring. Oxidative dearomatization, followed by Diels-Alder reaction, led to the 6/6-membered ring system, which was transformed into the 7/5-membered BC-ring through a stereospecific Wagner-Meerwein rearrangement. Finally, Hg(OAc)2 induced an oxidative aza-Prins cyclization to form the remaining 5-membered F-ring, thereby completing the chemical construction of 1.

Minagawa K., Kamakura D., Hagiwara K., Inoue M.

Talatisamine ( 1 ) is a C 19 -diterpenoid alkaloid with a synthetically challenging hexacyclic ABCDEF-ring structure. Herein we report a radical-based strategy for constructing the 6/7/5/6-membered ABCE-ring 8a . After assembling the 3 known fragments, an AE-ring, an allylstannane, and a C-ring, irradiation of the ACE-ring with Hg lamp in the presence of phenanthrene and 1,4-dicyanobenzene promoted decarboxylative formation of the C11-bridgehead radical, which cyclized into the 7-membered B-ring with stereoselective installation of the C9,10-tertiary carbons of 8a . • Talatisamine, a C19-diterpenoid alkaloid, has a complex 6/7/5/6/6/5-membered hexacyclic ABCDEF-ring skeleton. • We report the synthesis of 6/7/5/6-membered ABCE-ring framework from 3 simple components. • The 7-membered B-ring was constructed by utilizing a photoinduced decarboxylative radical reaction. • Phenanthrene and 1,4-dicyanobenzene enabled the formation of the hindered radical by single-electron oxidation.

Kamakura D., Todoroki H., Urabe D., Hagiwara K., Inoue M.

Kamakura D., Todoroki H., Urabe D., Hagiwara K., Inoue M.

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.

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.

Shi Y., Wilmot J.T., Nordstrøm L.U., Tan D.S., Gin D.Y.

The first total synthesis of the C18-norditerpenoid aconitine alkaloid neofinaconitine and relay syntheses of neofinaconitine and 9-deoxylappaconitine from condelphine are reported. A modular, convergent synthetic approach involves initial Diels–Alder cycloaddition between two unstable components, cyclopropene 10 and cyclopentadiene 11. A second Diels–Alder reaction features the first use of an azepinone dienophile (8), with high diastereofacial selectivity achieved via rational design of siloxydiene component 36 with a sterically demanding bromine substituent. Subsequent Mannich-type N-acyliminium and radical cyclizations provide complete hexacyclic skeleton 33 of the aconitine alkaloids. Key endgame transformations include the installation of the C8-hydroxyl group via conjugate addition of water to a putative strained bridghead enone intermediate 45 and one-carbon oxidative truncation of the C4 side chain to afford racemic neofinaconitine. Complete structural confirmation was provided by a concise relay synthesis of (+)-neofinaconitine and (+)-9-deoxylappaconitine from condelphine, with X-ray crystallographic analysis of the former clarifying the NMR spectral discrepancy between neofinaconitine and delphicrispuline, which were previously assigned identical structures.

Díaz J.G., Ruiza J.G., Herz W.

Aerial parts of Aconitum variegatum L. from the Pyrenees furnished four norditerpene alkaloids, 16 beta-hydroxycardiopetaline, 8-ethoxysachaconitine, 14-acetylgenicunine B, N-deethyl-N-19-didehydrosachaconitine, five diterpene alkaloids 15-veratroyldictizine, 15-veratroyl-17-acetyldictizine, 15-veratroyl-17-acetyl-19-oxodictizine, N-ethyl-1 alpha-hydroxy-17-veratroyldictizine, variegatine and the known alkaloids sachaconitine, 14-O-acetylsachaconitine, karakoline, talatizamine, 10-hydroxytalatizamine, 14-acetyltalatizamine, 14-acetyl-10-hydroxytalatizamine, N-methylarmepavine, pengshenin B, delsoline, dihydrodelsoline, delcosine and genicunin B. Structures of the alkaloids were established by MS, 1D- and 2D-NMR techniques.

Yue J., Xu J., Chen Y., Chen S.

From the root of Aconitum talassicum three new C 19 -diterpenoid alkaloids talassicumines, A, B and C, have been isolated and their structures elucidated on the basis of spectral evidence. Along with these new compounds, three known alkaloids songorine, cammaconine and aconorine have also been isolated.

Wang F., Liang X.

This chapter describes diterpenoid alkaloids as a group of highly oxygenated and complex natural compounds. They are divided into two broad categories, the norditerpenoid alkaloids based on a hexacyclic C19 skeleton and the diterpenoid alkaloids based on a number of C20 skeletons. The former is subdivided into four groups: the aconitine-type, lycoctonine-type, pyro-type, and lactone-type norditerpenoids. The diterpenoid alkaloids are also subdivided, mainly into three groups: the atisine, veatchine, and delnudine types. The term diterpenoid is occasionally used to cover both the C19 and C20 categories. The diterpenoid alkaloids have been studied for over 100 years. The chapter reviews the chemistry of diterpenoid alkaloids which lack explicit systematization according to reaction types. The chapter presents number of tables covering chemical reactions of diterpenoid alkaloids, showing the substrates, reaction conditions, products, yields, and key references. It discusses that yields are often the results of cursory observation; these tables are useful as a convenient point of departure for further studies on the chemistry of these alkaloids.

Pelletier S.W., Mody N.V.

Publisher Summary Since the early 1800s, the alkaloids (nitrogenous organic bases) isolated from plants of the Delphinium and Aconitum genera (Ranunculaceae) and more recently the Garrya genus (Garryaceae) and Inula royleana (Compositae) have been of interest because of their pharmacological properties, complex structures, and interesting chemistry. Biogenetically, these diterpenoid alkaloids are possibly formed in nature from tetracyclic or pentacyclic diterpenes in which the nitrogen atom of β -aminoethanol, methylamine, or ethylamine is linked to C-19 and C-20 in the C 20 -diterpenoid skeleton and C-17 and C-19 in the C 19 -diterpenoid skeleton to form a substituted piperidine ring. These diterpenoid alkaloids may be divided into two broad groups: those based on a hexacyclic C 19 -skeleton, and those based on a C 20 -skeleton. The C 19 -alkaloids are commonly called aconitines, and all possess the aconitine, the lycoctonine, or the heteratisine skeleton. Usually in the literature, the C 19 -diterpenoid alkaloids are referred to as either aconitinetype or lycoctonine-type alkaloids without structural differentiation. This practice sometimes creates confusion, therefore, this chapter has divided the C 19 -diterpenoid alkaloids into three categories, defined as follows: (1) Aconifine-type ; (2) Lycoctonine –type ; and (3) Heterutisine-type. These alkaloids possess the skeleton of heteratisine, in which a lactone moiety is always present.

Pelletier W., Mody N.V., Katsui N.