Total Synthesis, Relay Synthesis, and Structural Confirmation of the C18-Norditerpenoid Alkaloid Neofinaconitine

Yang Z., Chen Q., Wang F.

An AE azabicyclic fragment, with a β-hydroxyl group at C-5 and a substituent at C-1, of the C 19 -diterpenoid alkaloids, was synthesized. The key reactions include an intramolecular Claisen-type condensation, double Mannich reaction, and stereoselective nucleophilic addition of carbonyl group with the assistance of steric effect of 1β-substituent.

Nicolaou K.C., Adsool V.A., Hale C.R.

PhI(OAc)(2) in the presence of OsO(4) (cat.) and 2,6-lutidine cleaves olefinic bonds to yield the corresponding carbonyl compounds, albeit, in some cases, with alpha-hydroxy ketones as byproduct. A more practical and clean protocol to effect oxidative cleavage of olefinic bonds involves NMO, OsO(4) (cat.), 2,6-lutidine, and PhI(OAc)(2).

Wang F., Chen Q., Liu X.

The lasting attention that researchers have devoted to diterpenoid alkaloids is due to their various bioactivities and toxicities, structural complexity, and intriguing chemistry. From 1998 to the end of 2008, more than 300 new diterpenoid alkaloids were isolated from Nature. This review focuses on their structural relationships, and investigations into their chemical reactions, synthesis, and biological activities. A table that lists the names, plant sources, and structural types is given along with 363 references.

Wang F., Chen Q., Liang X.

For a long time, the C 18 -diterpenoid alkaloids were structurally classified as belonging to the broad group of C 19 -diterpenoid alkaloids. This chapter presents the first comprehensive overview of the C 18 -diterpenoid alkaloids as an independent group of alkaloids, as isolated from the three genera Aconitum , Delphinium , and Cosolida , all from the plant family Ranunculaceae. In this comprehensive discourse, the 78 naturally occurring C 18 -diterpenoid alkaloids reported in the literature till the end of July 2008 are presented in tables that include details pertaining to their classification and distribution, occurrence, structural features, and spectroscopic data and other physical properties, together with a cross-index. Their chemical reactions and pharmacological activities are also addressed in the later part of the chapter.

Hudon J., Cernak T., Ashenhurst J., Gleason J.

Conrad R.M., Du Bois J.

A strategy for the preparation of aconitine is described that attempts to exploit chemoselective C-H amination and the electrophilic reactivity of oxathiazinane N,O-acetals for assembling the complex, polycyclic carbon framework of the natural product.

Marzorati M., Hult K., Riva S., Danieli B.

A simple chemoenzymatic strategy for the incorporation of bioactive and suitably functionalized molecules into a polyester chain has been developed. The protocol involves first the reaction of a primary amine with E-caprolactone to give an amide carrying a terminal primary hydroxy group, followed by the enzymatic growth of the polymeric chain triggered by Novozym 435. This method is versatile and of different amines into polyesters, as has been shown with the model compounds benzylamine and tryptamine, the bioactive compound N-deacetylthiocolchicine and the functionalized propargylamine and tyramine.

Abdelrahman D., Benn M., Hellyer R., Parvez M., Edwards O.E.

The structure of a chromic acid oxidation product of the norditerpenoid alkaloid lycoctonine (1) was established as hydroxylycoctonal (3) by spectrometric analyses and X-ray crystallography of its reduction product, hydroxylycoctonine (5); the structure of lycoxonine, a chromic acid oxidation product of the lactam, lycoctonam (7), was similarly confirmed as N-ethyl-4,7,8-trihydroxy-1α,6β,14α,16β-tetramethoxy-19-oxoaconitane (8). Reduction of lycoxonine with lithium aluminium hydride gave the 1,14-di-O-methyl ether (12) of the bisnorditerpenoid alkaloid delbine (9).Key words: norditerpenoid, bisnorditerpenoid, alkaloids, lycoctonine, lycoctonam, hydroxylycoctonal, lycoxonine. 1,14-di-O-methyldelbine, semisynthesis.

Taber D.F., Liang J., Chen B., Cai L.

[reaction: see text] A model study leading to the preparation of the AEF rings of N-deacetyllappaconitine is described. The conjugate addition to the alpha-alkyl cyclohexenone 10 proceeded with high diastereocontrol. The Mannich cyclization of 16 to 4 was accomplished by heating with Rexyn-300 and Na(2)SO(4).

Barker D., Brimble M.A., McLeod M.D.

The synthesis of several A and AE ring analogues of the alkaloid methyllycaconitine is reported. The key 2-(2″-methylsuccinimido)benzoate ester pharmacophore is introduced using an efficient two step procedure. Esterification of the alcohol precursors with N-(trifluoroacetyl)anthranilic acid under Steglich conditions followed by sodium borohydride mediated cleavage of the trifluoroacetyl group affords the anthranilate esters. Subsequent fusion with methylsuccinic anhydride affords the N-substituted anthranilate derivatives containing the key pharmacophore present in a range of commonly occurring Delphinium and Aconitum alkaloids.

Zhou G., Hu Q., Corey E.J.

[reaction: see text] Nine examples are reported of enantioselective [4 + 2] cycloaddition reactions of achiral, acyclic substrates to form chiral bicyclo[4.3.0]nonane or bicyclo[4.4.0]decane derivatives.

Hiyamizu H., Ooi H., Inomoto Y., Esumi T., Iwabuchi Y., Hatakeyama S.

[figure: see text] This report describes a concise enantioselective synthesis of the A-ring synthon for the synthesis of 1 alpha-hydroxyvitamin D3 compounds. The synthesis involves two notable transformations: (I) stereoselective construction of the enol triflate from the vinyl ketone by Michael addition of Ph2P(O)Li followed by in situ triflation of the resulting enolate and (II) palladium-catalyzed Heck type cyclization of the enol triflate.

Ulubelen A., Meriçli A.H., Meriçli F., Kolak U.(., Ilarslan R., Voelter W.

From the aerial parts of Delphinium crispulum five known norditerpenoid alkaloids, deltatsine, browniine, karakoline, ezochasmanine and isotalatizidine, and the C 20 alkaloid hetisine as well as two new compounds, crispulidine and delphicrispuline, were isolated. Structures of the newly isolated alkaloids were established by spectroscopic methods.

Ameri A.

Preparations of Aconitum roots are employed in Chinese and Japanese medicine for analgesic, antirheumatic and neurological indications. The recent surge in use of phytomedicine derived from traditional Chinese medicine as well as increasing concerns about possible toxic effects of these compounds have inspired a great deal of research into the mechanisms by which certain Aconitum alkaloids may act on the central nervous system. The pharmacological effects of preparations of Aconitum roots are attributed to several diterpenoid alkaloids. The main alkaloid of these plants is aconitine, a highly toxic diterpenoid alkaloid which is known to suppress the inactivation of voltage-dependent Na+ channels by binding to neurotoxin binding site 2 of the alpha-subunit of the channel protein. In this article the pharmacology of several structurally related Aconitum alkaloids is highlighted and their therapeutic vs toxic potential is discussed. Neurochemical and neurophysiological studies will be reviewed with emphasis on the effects of the alkaloids in regions of the brain that have been implicated in pain transmission and generation of epileptic activity. Considering the chemical structure of the Aconitum alkaloids as well as their mechanism of action, a subdivision in three groups becomes obvious: the first group comprises such alkaloids which possess high toxicity due to two ester boundings at the diterpene skeleton. The members of this group activate voltage-dependent sodium channels already at resting potential and inhibit noradrenaline reuptake. Activation of sodium channels and in consequence excessive depolarization with final inexcitability and suppression of pain transmission account for their antinociceptive properties. The second group comprises less toxic monoesters which have been shown to possess strong antinociceptive, antiarrhythmic and antiepileptiform properties due to a blockade of the voltage-dependent sodium channel. Electrophysiological studies have revealed a use-dependent inhibition of neuronal activity by these alkaloids. They seem to be competitive antagonists of the group I-alkaloids. The third group of Aconitum alkaloids are lacking an ester side chain in the molecule. Toxicity is markedly reduced when compared with the two other groups. They fail to affect neuronal activity, but are reported to have antiarrhythmic actions suggesting that they may have different affinities to various subtypes of the alpha-subunit of the Na+ channel in brain and heart.

Curran T.T., Hay D.A., Koegel C.P., Evans J.C.

The preparation and enzymatic resolution of several cis-mono-4-O-protected-2-cyclopenten-1,4-diols are described. The process starts with inexpensive furfuryl alcohol and lends itself to the preparation of multigram quantities of various protected, optically active 2-cyclopenten-1,4-diol derivatives. Stereoselective reduction of 4-O-protected-2-cyclopentenone to the cis-mono-O-protected-2-cyclopenten-1,4-diol using LiAlH 4 LiI or Red-Al • NaI is described. Subsequent pancreatin-promoted, stereoselective acylation was conducted on these cis-(+/−)-mono-O-protected-cyclopenten-1,4-diols to afford the corresponding alcohols and acetates in moderate to excellent enantioselectivities.

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.

Kage M., Yamakoshi H., Tabata M., Ohashi E., Noguchi K., Watanabe T., Uchida M., Takada M., Ikeuchi K., Nakamura S.

An oxidative method for generation of isobenzofurans from phthalans, which enables the formal synthesis of morphine, has been developed.

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.

Lu F., Shao Y., Yan S., Yang D., Song H., Zhang D., Liu X., Qin Y.

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.

Shao H., Liu W., Liu M., He H., Zhou Q., Zhu S., Gao S.

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.

Li Q., Zhang G., Wang F., Cen Y., Liu X., Zhang J., Wang Y., Lee A.W., Gao D., Lin G., Tian P.

In nature, cyclopropylcarbinyl cation is often involved in cationic cascade reactions catalyzed by natural enzymes to produce a great number of structurally diverse natural substances. However, mimicking this natural process with artificial organic catalysts remains a daunting challenge in synthetic chemistry. We report a small molecule–catalyzed asymmetric rearrangement of cyclopropylcarbinyl cations, leading to a series of chiral homoallylic sulfide products with good to excellent yields and enantioselectivities (up to 99% enantiomeric excess). In the presence of a chiral SPINOL-derived N -triflyl phosphoramide catalyst, the dehydration of prochiral cyclopropylcarbinols occurs rapidly to generate symmetrical cyclopropylcarbinyl cations, which are subsequently trapped by thione-containing nucleophiles. A subgram-scale experiment and multiple downstream transformations of the sulfide products are further pursued to demonstrate the synthetic utility. Notably, a few heteroaromatic sulfone derivatives could serve as “covalent warhead” in the enzymatic inhibition of severe acute respiratory syndrome coronavirus 2 main protease.

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.

Kirsanov V.Y., Rakhimova E.B.

This review is devoted to the analysis of works published over the past 20 years on the chemistry of saturated annulated nitrogen-containing polycyclic compounds, the molecules of which consist of four, five, six, and seven cycles, and contain from one to eight endocyclic nitrogen atoms.

Liu X., Ke B., Qin Y., Wang F.

The diterpenoid alkaloids are a family of extremely important natural products that have long been a research hotspot due to their myriad of intricate structures and diverse biological properties. This chapter systematically summarizes the past 11 years (2009-2019) of studies on the diterpenoid alkaloids, including the "so-called" atypical ones, covering the classification and biogenetic relationships, phytochemistry together with 444 new alkaloids covering 32 novel skeletons and the corrected structures, chemical reactions including conversion toward toxoids, synthetic studies, as well as biological activities. It should be noted that the synthetic studies, especially the total syntheses of various diterpenoid alkaloids, are for the first time reviewed in this treatise. This chapter, in combination with our four previous reviews in volumes 42, 59, 67, and 69, will present to the readers a more completed and updated profile of the diterpenoid alkaloids.

Xu J., Li Y., Huang S., Chen L., Luo Y., Gao F., Zhou X.

Seven previously undescribed diterpenoid alkaloids, eight reaction products and thirteen known compounds were isolated from the whole plant of Delphinium grandiflorum L. (Ranunculaceae). Grandiflonines A and B have an unprecedented C 20 –diterpenoid alkaloid skeleton, which features inversion of the configuration of C–18. Their structures were determined by comprehensive analyses of spectroscopic data, X–ray diffraction and Mosher's method. The probable biosynthetic pathway of grandiflonine A was discussed. Additionally, the analgesic activity and anti–inflammatory activity by inhibition of NO production were evaluated. Among them, deoxylappaconitine (ED 50 = 0.35 mg/kg, TI = 46.22) showed significant analgesic activity that was superior to the reference drug lappaconitine (ED 50 = 3.5 mg/kg, TI = 3.34). • Seven undescribed diterpenoid alkaloids, eight reaction products and thirteen known compounds were isolated from Delphinium grandiflorum L. • Grandiflonines A and B have an unprecedented C 20 –diterpenoid alkaloid skeleton. • Deoxylappaconitine (ED 50 = 0.35 mg/kg, TI = 46.22) showed a significant analgesic activity superior to the reference drug lappaconitine.