Vallesamidine and schizozygane alkaloids: rearranged monoterpene indole alkaloids and synthetic endeavours.

Covering 1963 to 2023Monoterpene indole alkaloids are the main sub-family of indole alkaloids with fascinating structures, stereochemistry, and diverse bioactivities (e.g., anticancer, anti-malarial and anti-arrhythmic etc.). Vallesamidine alkaloids and structurally more complex schizozygane alkaloids are small groups of rearranged monoterpene indole alkaloids with a unique 2,2,3-trialkylated indoline scaffold, while schizozygane alkaloids can generate a further rearranged skeleton, isoschizozygane, possessing a tetra-substituted, bridged tetrahydroquinoline core. In this review, the origin and structural features of vallesamidine and schizozygane alkaloids are introduced, and a discussion on the relationship of these alkaloids with aspidosperma alkaloids and a structural rearrangement hypothesis based on published studies is followed. Moreover, uncommon skeletons and potential bioactivities, such as anti-malarial and anti-tumour activities, make such alkaloids important synthetic targets, attracting research groups globally to accomplish total synthesis, resulting in impressive works on novel total synthesis, formal synthesis, and construction of key intermediates. These synthetic endeavours are systematically reviewed and highlighted with key strategies and efficiencies, providing different viewpoints on molecular structures and promoting the extension of chemical space and mining of new active scaffolds.

Semisynthesis of Bis-Indole Alkaloid (-)-Melodinine K Enabled by a Combination of Biotransformation and Chemical Synthesis.

Enzymatic biotransformation has become a widely used technique in synthetic chemistry to achieve difficult chemical transformations. Cytochrome P450 monooxygenase enzymes found in nature carry out a wide range of difficult chemical reactions, such as the oxidation of the monoterpene indole alkaloid (-)-tabersonine at the unreactive 16th position on the indoline benzene ring in the biosynthesis of biologically active natural products such as the bis-indole alkaloid (-)-melodinine K. Herein, we describe the first semisynthesis of (-)-melodinine K enabled by a biological gram scale route to the northern fragment, (-)-16-hydroxytabersonine, as well as a chemical route to the southern fragment, (-)-pachysiphine, both derived from (-)-tabersonine and subsequently coupled in only eight linear steps. (-)-16-Hydroxytabersonine is produced through an enzymatic biotransformation with a genetically modified Saccharomyces cerevisiae yeast strain expressing a tabersonine 16-hydroxylase enzyme to enable regioselective oxidation on multigram scale, and (-)-pachysiphine is produced through stereoselective and regioselective epoxidation of the disubstituted alkene.

Structure units oriented approach towards collective synthesis of sarpagine-ajmaline-koumine type alkaloids.

Sarpagine-Ajmaline-Koumine type monoterpenoid indole alkaloids represent a fascinating class of natural products with polycyclic and cage-like structures, interesting biological activities, and related biosynthetic origins. Herein we report a unified approach towards the asymmetric synthesis of these three types of alkaloids, leading to a collective synthesis of 14 natural alkaloids. Among them, akuammidine, 19-Z-akuammidine, vincamedine, vincarine, quebrachidine, vincamajine, alstiphylianine J, and dihydrokoumine are accomplished for the first time. Features of our synthesis are a new Mannich-type cyclization to construct the key indole-fused azabicyclo[3.3.1]nonane common intermediate, a SmI2 mediated coupling to fuse the aza-bridged E-ring, stereoselective olefinations to install either the 19-E or 19-Z terminal alkenes presented in the natural alkaloids, and an efficient iodo-induced cyclization to establish the two vicinal all-carbon quaternary centers in the Koumine-type alkaloids.

Design, synthesis and biological evaluation of novel evodiamine and rutaecarpine derivatives against phytopathogenic fungi.

Evodiamine and rutaecarpine are two alkaloids isolated from traditional Chinese herbal medicine Evodia rutaecarpa, which have been reported to have various biological activities in past decades. To explore the potential applications for evodiamine and rutaecarpine alkaloids and their derivatives, various kinds of evodiamine and rutaecarpine derivatives were designed and synthesized. Their antifungal profile against six phytopathogenic fungi Rhizoctonia solani, Botrytis cinerea, Fusarium graminearum, Fusarium oxysporum, Sclerotinia sclerotiorum, and Magnaporthe oryzae were evaluated for the first time. Furthermore, a series of modified imidazole derivatives of rutaecarpine were synthesized to investigate the structure-activity relationship. The results of antifungal activities in vitro showed that imidazole derivative of rutaecarpine A1 exhibited broad-spectrum inhibitory activities against R. solani, B. cinerea, F. oxysporum, S. sclerotiorum, M. oryzae and F. graminearum with EC50 values of 1.97, 5.97, 12.72, 2.87 and 16.58 µg/mL, respectively. Preliminary mechanistic studies showed that compound A1 might cause mycelial abnormalities of S. sclerotiorum, mitochondrial distortion and swelling, and inhibition of sclerotia formation and germination. Moreover, the curative effects of compound A1 were 94.7%, 81.5%, 80.8%, 65.0% at 400, 200, 100, 50 µg/mL in vivo experiments, which was far more effective than the positive control azoxystrobin. Significantly, no phytotoxicity of compound A1 on oilseed rape leaves was observed obviously even at a high concentration of 400 µg/mL. Therefore, compound A1 is expected to be a novel leading structure for the development of new antifungal agents.

Design, synthesis and biological evaluation of bisindole derivatives as anticancer agents against Tousled-like kinases.

This study presents the design, synthesis, and characterization of bisindole molecules as anti-cancer agents against Tousled-like kinases (TLKs). We show that compound 2 composed of an indirubin-3'-oxime group linked with a (N-methylpiperidin-2-yl)ethyl moiety possessed inhibitory activity toward both TLK1 and TLK2 in vitro and diminished the phosphorylation level of the downstream substrate anti-silencing function 1 (ASF1) in replicating cells. The treatment of compound 2 impaired DNA replication, slowed S-phase progression, and triggered DNA damage response in replicating cells. Structure optimization further discovered six derivatives exhibiting potent TLK inhibitory activity and revealed the importance of the tertiary amine-containing moiety of the side chain. Moreover, the derivatives 6, 17, 19, and 20 strongly suppressed the growth of triple-negative breast cancer MDA-MB-231 cells, non-small cell lung cancer A549 cells, and colorectal cancer HCT-116 cells, while normal lung fibroblast MRC5 and IMR90 cells showed a lower response to these compounds. Taken together, this study identifies tertiary amine-linked indirubin-3'-oximes as potent anticancer agents that inhibit TLK activity.

Total synthesis of (±)-decursivine via BINOL-phosphoric acid catalyzed tandem oxidative cyclization.

The synthesis of tetracyclic indole alkaloid (±)-decursivine was accomplished using BINOL-phosphoric acid catalyzed tandem oxidative cyclization as a key step with (bis(trifluoroacetoxy)iodo)benzene (PIFA) as an oxidizing agent. This represents one of the shortest and highest yielding routes for the synthesis of (±)-decursivine from readily available starting materials.

A Chiral-Pool-Based Strategy to Access trans-syn-Fused Drimane Meroterpenoids: Chemoenzymatic Total Syntheses of Polysin, N-Acetyl-polyveoline and the Chrodrimanins.

trans-syn-Fused drimane meroterpenoids are unique natural products that arise from contra-thermodynamic polycyclizations of their polyene precursors. Herein we report the first total syntheses of four trans-syn-fused drimane meroterpenoids, namely polysin, N-acetyl-polyveoline, chrodrimanin C, and verruculide A, in 7-18 steps from sclareolide. The trans-syn-fused drimane unit is accessed through an efficient acid-mediated C9 epimerization of sclareolide. Subsequent applications of enzymatic C-H oxidation and contemporary annulation methodologies install the requisite C3 hydroxyl group and enable rapid generation of structural complexity to provide concise access to these natural products.

Total Synthesis of (-)-Picrinine, (-)-Scholarisine C, and (+)-5-ß-Methoxyaspidophylline.

The first asymmetric total synthesis of three picrinine-type akuammiline alkaloids, (-)-picrinine, (-)-scholarisine C, and (+)-5-ß-methoxyaspidophylline, has been accomplished. The synthesis features an efficient acid-promoted oxo-bridge ring-opening and further carbonyl O-cyclization to assemble the furoindoline scaffold, an unusual Dauben-Michno oxidation to construct the requisite α,ß-unsaturated aldehyde functionality, and a nickel-mediated reductive Heck reaction to forge the [3.3.1]-azabicyclic core.

[Synthetic Study of Polycyclic Natural Products Based on Development of New Strategy].

On the occasion of receiving the Pharmaceutical Society of Japan Award 2020, I explained our research activities on the total syntheses of polycyclic alkaloids as an invited review. The structure of lundurine B, which has an unstable cyclopropane fused indoline skeleton, was proved firstly by the total synthesis. I also describe the total syntheses of optically active lundurine B and rapidilectine B utilizing asymmetric desymmetrization of the spiro intermediate. We developed an intramolecular bond formation reaction between the 2-position of the furan ring to the iminium cation (furane-iminium cation cyclization) to synthesize manzamine alkaloids. The reaction was applied to the total synthesis of the core skeleton of nakadomarin A and ircinal A. A ring-closing metathesis reaction effectively applied to the synthesis of medium and large heterocyclic rings containing the cis double bond found in the structures of nakadomarin A and ircinal A. The total synthesis of schizocommunin, a metabolite of Schizophyllum commune isolated from a patient with human allergenic bronchopulmonary mycosis, was accomplished. We could correct the error in the proposed structure by total synthesis of the natural product. A part of the mechanism of cytotoxicity expression was clarified using newly synthesized shizocommunin.

Structure Reassignment of Melonine and Quantum-Chemical Calculations-Based Assessment of Biosynthetic Scenarios Leading to Its Revised and Original Structures.

Melonine is a basic monoterpene indole alkaloid (MIA) skeleton from Melodinus philliraeoides that was reported in 1983. The scarcity of its spectroscopic data questioned the validity of its structure. This prompted us to reisolate this molecule and to revise its structure into an unprecedented MIA scaffold. DFT-validated biosynthetic paths to both this new core and the originally reported form are proposed. The pathway to the original structure of melonine seems to be thermodynamically feasible, and that compound may exist as a natural product.

Structural basis of the stereoselective formation of the spirooxindole ring in the biosynthesis of citrinadins.

Prenylated indole alkaloids featuring spirooxindole rings possess a 3R or 3S carbon stereocenter, which determines the bioactivities of these compounds. Despite the stereoselective advantages of spirooxindole biosynthesis compared with those of organic synthesis, the biocatalytic mechanism for controlling the 3R or 3S-spirooxindole formation has been elusive. Here, we report an oxygenase/semipinacolase CtdE that specifies the 3S-spirooxindole construction in the biosynthesis of 21R-citrinadin A. High-resolution X-ray crystal structures of CtdE with the substrate and cofactor, together with site-directed mutagenesis and computational studies, illustrate the catalytic mechanisms for the possible ß-face epoxidation followed by a regioselective collapse of the epoxide intermediate, which triggers semipinacol rearrangement to form the 3S-spirooxindole. Comparing CtdE with PhqK, which catalyzes the formation of the 3R-spirooxindole, we reveal an evolutionary branch of CtdE in specific 3S spirocyclization. Our study provides deeper insights into the stereoselective catalytic machinery, which is important for the biocatalysis design to synthesize spirooxindole pharmaceuticals.

Total Synthesis of (-)-Strempeliopine.

A total synthesis of (-)-strempeliopine is disclosed that enlists a powerful SmI2-mediated and BF3·OEt2-initiated dearomative transannular radical cyclization onto an indole by an N-acyl α-aminoalkyl radical that is derived by single electron reduction of an in situ generated iminium ion for formation of a quaternary center and the strategic C19-C2 bond in its core structure.

Total Synthesis of the Chlorinated Pentacyclic Indole Alkaloid (+)-Ambiguine G.

Reported herein is the total synthesis of (+)-ambiguine G, the first member of the chlorinated pentacyclic ambiguines to yield to chemical synthesis. The synthesis is accomplished through a convergent strategy that proceeds in 10 steps from (S)-carvone oxide. Pivotal to the concise route is the successful realization of a [4+3] cycloaddition that conjoins two easily synthesized components of the carbon framework of the natural product. Also featured in the synthesis is the efficient, diastereoselective construction of a key vinylated chloro ketone and the unprecedented, one-pot reduction-elimination-oxidation sequence that transforms an enone to an advanced hydroxylated-diene intermediate.

Total Synthesis of Nortopsentin D via a Late-Stage Pinacol-like Rearrangement.

Nortopsentin D is part of a class of bis(indole) alkaloids known for their biological activity, including inhibitory activity in tumoral cells and antifungal activity. Herein we describe the first total synthesis of nortopsentin D, in which amidine and dione undergo a pivotal condensation and subsequent cyclization via a pinacol-like rearrangement. This synthesis represents a unique strategy for the formation of 5,5-disubstituted (4H)-imidazol-4-one containing natural products, many of which have yet to succumb to total synthesis.

The Enantioselective Synthesis of Eburnamonine, Eucophylline, and 16'-epi-Leucophyllidine.

A synthetic approach to the heterodimeric bisindole alkaloid leucophyllidine is disclosed herein. An enantioenriched lactam building block, synthesized through palladium-catalyzed asymmetric allylic alkylation, served as the precursor to both hemispheres. The eburnamonine-derived fragment was synthesized through a Bischler-Napieralski/hydrogenation approach, while the eucophylline-derived fragment was synthesized by Friedländer quinoline synthesis and two sequential C-H functionalization steps. A convergent Stille coupling and phenol-directed hydrogenation united the two monomeric fragments to afford 16'-epi-leucophyllidine in 21 steps from commercial material.

Nonbiomimetic total synthesis of indole alkaloids using alkyne-based strategies.

Biomimetic natural product synthesis is generally straightforward and efficient because of its established feasibility in nature and utility in comprehensive synthesis, and the cost-effectiveness of naturally derived starting materials. On the other hand, nonbiomimetic strategies can be an important option in natural product synthesis since (1) nonbiomimetic synthesis offers more flexibility and can demonstrate the originality of chemists, and (2) the structures of derivatives accessible by nonbiomimetic synthesis can be considerably different from those that are synthesised in nature. This review summarises nonbiomimetic total syntheses of indole alkaloids using alkyne chemistry for constructing core structures, including ergot alkaloids, monoterpene indole alkaloids (mainly corynanthe, aspidosperma, strychnos, and akuammiline), and pyrroloindole and related alkaloids. To clarify the differences between alkyne-based strategies and biosynthesis, the alkynes in nature and the biosyntheses of indole alkaloids are also outlined.

Asymmetric Total Synthesis of Sarpagine and Koumine Alkaloids.

We report here a concise, collective, and asymmetric total synthesis of sarpagine alkaloids and biogenetically related koumine alkaloids, which structurally feature a rigid cage scaffold, with L-tryptophan as the starting material. Two key bridged skeleton-forming reactions, namely tandem sequential oxidative cyclopropanol ring-opening cyclization and ketone α-allenylation, ensure concurrent assembly of the caged sarpagine scaffold and installation of requisite derivative handles. With a common caged intermediate as the branch point, by taking advantage of ketone and allene groups therein, total synthesis of five sarpagine alkaloids (affinisine, normacusine B, trinervine, Na -methyl-16-epipericyclivine, and vellosimine) with various substituents and three koumine alkaloids (koumine, koumimine, and N-demethylkoumine) with more complex cage scaffolds has been accomplished.

Enantioselective Total Synthesis of (+)-Alstilobanine†C, (+)-Undulifoline, and (-)-Alpneumine†H.

We report herein the enantioselective total synthesis of three monoterpene indole alkaloids, namely, (+)-alstilobanine C, (+)-undulifoline, and (-)-alpneumine H. The key features of our synthesis include: a) introduction of chirality via enantioselective deprotonation of a prochiral 4-substituted cyclohexanone; b) use of methoxymethyl (MOM) ether as both a hydroxyl protective group and a latent oxonium species for the formation of bridged oxepane and c) domino double reductive cyclization to build both the indole and the piperidine ring at the end of the synthesis. The synthesis confirmed the absolute configuration of these natural products assigned based on the biogenetic hypothesis.

The chemistry of mavacurane alkaloids: a rich source of bis-indole alkaloids.

Covering: since early reports up to the end of 2020This review presents a complete coverage of the mavacuranes alkaloids since early reports till date. Mavacuranes alkaloids are a restrictive sub-group of monoterpene indole alkaloids (MIAs), which are represented by their two emblematic congeners, namely, C-mavacurine and pleiocarpamine. Their skeleton is defined by a bond between the indolic N1 nitrogen and the C16 carbon of the tetracyclic scaffold of the corynanthe group in MIA. A limited number of congeners is known as this skeleton can be considered as a cul-de-sac in main MIA biosynthetic routes. Thanks to the enhanced enamine-type reactivity, mavacuranes are frequently involved in the formation of multimeric MIA scaffolds. This review covers isolation aspects and synthetic approaches towards the mavacurane core and bisindole assemblies. To access the mavacurane core, only a few strategies are reported and the main synthetic difficulties usually originate from the important rigidity of the pentacyclic system. For the bisindole assemblies, biomimetic routes are privileged and deliver complex structures using smooth conditions.

Bioinspired Early Divergent Oxidative Cyclizations toward Pleiocarpamine, Talbotine, and Strictamine.

Toward the mavacurane and akuammilane monoterpene indole alkaloids, we developed divergent oxidative couplings between the indole nucleus (at N1 or C7) and the C16-malonate of a common tricyclic model related to strictosidine according to a biosynthetic hypothesis postulated by Hesse and Schmid. These oxidative cyclizations led selectively to the formation of the N1-C16 bond of pleiocarpamine or to the C7-C16 bond of strictamine. We were then able to obtain the scaffold of talbotine.