Synthesis Of Alkaloids Research Articles

Convergent and Efficient Total Synthesis of (+)-Heilonine Enabled by C-H Functionalizations.

We report a convergent and efficient total synthesis of the C-nor D-homo steroidal alkaloid (+)-heilonine with a hexacyclic ring system, nine stereocenters, and a trans-hydrindane moiety. Our synthesis features four selective C-H functionalizations to form key C-C bonds and stereocenters, a Stille carbonylative cross-coupling to connect the AB ring system with the DEF ring system, and a Nazarov cyclization to construct the five-membered C ring. These enabling transformations significantly reduced functional group manipulations and delivered (+)-heilonine in 11 or 13 longest linear sequence (LLS) steps.

Genome-wide identification of the alkaloid synthesis gene family CYP450, gives new insights into alkaloid resource utilization in medicinal Dendrobium

The medicinal Dendrobium species of Orchidaceae possess significant pharmaceutical value, and modern pharmacological research has shown that Dendrobium contains many important active ingredients. Alkaloids, the crucial components of medicinal Dendrobium, demonstrate beneficial healing properties in cardiovascular, cataract, gastrointestinal, and respiratory diseases. Members of the cytochrome P450 monooxygenase (CYP) gene family play essential roles in alkaloid synthesis, participating in alkaloid terpene skeleton construction and subsequent modifications. Although studies of the CYP family have been conducted in some species, genome-wide characterization and systematic analysis of the CYP family in medicinal Dendrobium remain underexplored. In this study, we identified CYP gene family members in the genomes of four medicinal Dendrobium species recorded in the Pharmacopoeia: D. nobile, D. chrysotoxum, D. catenatum, and D. huoshanense. Further, we analyzed the motif composition, gene replication events, and selection pressure of this family. Syntenic analysis revealed that members of the clan 710 were present on chromosome 18 in three medicinal Dendrobium species, except for D. nobile, indicating a loss of clan 710 occurring in D. nobile. We also conducted an initial screening of the CYP genes involved in alkaloid synthesis through transcriptome sequencing. Quantitative real-time reverse transcription PCR showed that the expression of DnoNew43 and DnoNew50, homologs of secologanin synthase involved in the alkaloid synthesis pathway, was significantly higher in the stems than in the leaves. This result coincided with the distribution of dendrobine content in Dendrobium stems and leaves, indicating that these two genes might be involved in the dendrobine synthesis pathway. Our results give insights into the CYP gene family evolution analysis in four medicinal Dendrobium species for the first time and identify two related genes that may be involved in alkaloid synthesis, providing a valuable resource for further investigations into alkaloid synthesis pathway in Dendrobium and other medicinal plants.

The CYP80A and CYP80G Are Involved in the Biosynthesis of Benzylisoquinoline Alkaloids in the Sacred Lotus (Nelumbo nucifera).

Bisbenzylisoquinoline and aporphine alkaloids are the two main pharmacological compounds in the ancient sacred lotus (Nelumbo nucifera). The biosynthesis of bisbenzylisoquinoline and aporphine alkaloids has attracted extensive attention because bisbenzylisoquinoline alkaloids have been reported as potential therapeutic agents for COVID-19. Our study showed that NnCYP80A can catalyze C-O coupling in both (R)-N-methylcoclaurine and (S)-N-methylcoclaurine to produce bisbenzylisoquinoline alkaloids with three different linkages. In addition, NnCYP80G catalyzed C-C coupling in aporphine alkaloids with extensive substrate selectivity, specifically using (R)-N-methylcoclaurine, (S)-N-methylcoclaurine, coclaurine and reticuline as substrates, but the synthesis of C-ring alkaloids without hydroxyl groups in the lotus remains to be elucidated. The key residues of NnCYP80G were also studied using the 3D structure of the protein predicted using Alphafold 2, and six key amino acids (G39, G69, A211, P288, R425 and C427) were identified. The R425A mutation significantly decreased the catalysis of (R)-N-methylcoclaurine and coclaurine inactivation, which might play important role in the biosynthesis of alkaloids with new configurations.

Spatio-temporal variation in synthesis of some nutraceutical components of thorowax foldwing (Dicliptera bupleuroides Nees)

The present research was carried out to determine the spatiotemporal variation in accumulation of different nutritional and medicinal components in Dicliptera bupleuroides from the Soone valley in the Salt Range of Punjab, Pakistan. Most of the biochemical attributes were higher in the spring season than those in the other seasons; this might have been due to high soil pH during spring. High amounts of minerals and high pH are necessary for the synthesis of alkaloids, phenols, flavonoids, and fibers. Proteins, N, dry matter, fats and nitrogen free extract (NFE) were higher in summer, which might have been due to considerable availability of macro-nutrients during this season due to high moisture content because of high rainfall during the season. Spatial variation showed that phenols and flavonoids were associated with the population from Khabeki site (despite enough minerals and moisture availability) which might have been due to physical injuries caused by grazing and cutting. Minerals, proteins and N were also associated with the Khabeki population probably due to large amounts of minerals and moisture retention in the soil of the site and prevalent optimum environmental conditions therein. Alkaloids, fats, moisture and some minerals were associated with Anga and Knotti Garden sites which might have been due to high pH and prolonged salt stressed conditions at both sites.

Exploring the synthetic potential of epoxide ring opening reactions toward the synthesis of alkaloids and terpenoids: a review.

Epoxides are oxygen containing heterocycles which are significantly employed as crucial intermediates in various organic transformations. They are considered highly reactive three-membered heterocycles due to ring strain and they undergo epoxide ring opening reactions with diverse range of nucleophiles. Epoxide ring-opening reactions have gained prominence as flexible and effective means to obtain various functionalized molecules. These reactions have garnered substantial attention in organic synthesis, driven by the need to comprehend the synthesis of biologically and structurally important organic compounds. They have also found applications in the synthesis of complex natural products. In this review article, we have summarized the implementation of epoxide ring opening reactions in the synthesis of alkaloids and terpenoids based natural products reported within the last decade (2014-2023).

Retraction: Recent advances in total synthesis of protoberberine and chiral tetrahydroberberine alkaloids.

Retraction of 'Recent advances in total synthesis of protoberberine and chiral tetrahydroberberine alkaloids' by Zhen-Xi Niu et al., Nat. Prod. Rep., 2024, https://doi.org/10.1039/d4np00016a.

Recent advances in total synthesis of protoberberine and chiral tetrahydroberberine alkaloids.

Covering: Up to 2024Due to the widespread distribution of protoberberine alkaloids (PBs) and tetrahydroberberine alkaloids (THPBs) in nature, coupled with their myriad unique physiological activities, they have garnered considerable attention from medical practitioners. Over the past few decades, synthetic chemists have devised various total synthesis methods to attain these structures, continually expanding reaction pathways to achieve more efficient synthetic strategies. Simultaneously, the chiral construction of THPBs has become a focal point. In this comprehensive review, we categorically summarized the developmental trajectory of the total synthesis of these alkaloids based on the core closure strategies of protoberberine and tetrahydroberberine.

Uncovering the mechanism of Clostridium butyricum CBX 2021 to improve pig health based on in vivo and in vitro studies.

As a symbiotic probiotic for the host, Clostridium butyricum (CB) has the potential to strengthen the body's immune system and improve intestinal health. However, the probiotic mechanism of CB is not completely understood. The Clostridium butyricum CBX 2021 strain isolated by our team from a health pig independently exhibits strong butyric acid production ability and stress resistance. Therefore, this study comprehensively investigated the efficacy of CBX 2021 in pigs and its mechanism of improving pig health. In this study, we systematically revealed the probiotic effect and potential mechanism of the strain by using various methods such as microbiome, metabolites and transcriptome through animal experiments in vivo and cell experiments in vitro. Our in vivo study showed that CBX 2021 improved growth indicators such as daily weight gain in weaned piglets and also reduced diarrhea rates. Meanwhile, CBX 2021 significantly increased immunoglobulin levels in piglets, reduced contents of inflammatory factors and improved the intestinal barrier. Subsequently, 16S rRNA sequencing showed that CBX 2021 treatment implanted more butyric acid-producing bacteria (such as Faecalibacterium) in piglets and reduced the number of potentially pathogenic bacteria (like Rikenellaceae RC9_gut_group). With significant changes in the microbial community, CBX 2021 improved tryptophan metabolism and several alkaloids synthesis in piglets. Further in vitro experiments showed that CBX 2021 adhesion directly promoted the proliferation of a porcine intestinal epithelial cell line (IPEC-J2). Moreover, transcriptome analysis revealed that bacterial adhesion increased the expression of intracellular G protein-coupled receptors, inhibited the Notch signaling pathway, and led to a decrease in intracellular pro-inflammatory molecules. These results suggest that CBX 2021 may accelerate piglet growth by optimizing the intestinal microbiota, improving metabolic function and enhancing intestinal health.

Divergent total syntheses of pyrroloiminoquinone alkaloids enabled by the development of a Larock/Buchwald-Hartwig annulation/cyclization.

Pyrroloiminoquinone alkaloids are a large class of natural products that display a wide range of biological activities. Synthetic approaches to these natural products typically rely on a common late-stage C10-oxygenated pyrroloiminoquinone intermediate, but these strategies often lead to lengthy synthetic sequences that are not amenable to divergent syntheses. We devised an alternative approach aimed at the early introduction of the C10 nitrogen, which we hypothesized would enable late-stage diversification. This strategy hinged upon a Larock/Buchwald-Hartwig annulation/cyclization to quickly access the core of these alkaloids. We report the development of this cascade process, which was facilitated by a dual ligand system in addition to selective functionalization of the key intermediate, to provide efficient syntheses of makaluvamines A, C, and D and isobatzelline B, and the first total synthesis of makaluvamine N.

Isolation, biological activity, and synthesis of isoquinoline alkaloids.

Covering: 2019 to 2023Isoquinoline alkaloids, an important class of N-based heterocyclic compounds, have attracted considerable attention from researchers worldwide. To follow up on our prior review (covering 2014-2018) and present the progress of this class of compounds, this review summarizes and provides updated literature on novel isoquinoline alkaloids isolated during the period of 2019-2023, together with their biological activity and underlying mechanisms of action. Moreover, with the rapid development of synthetic modification strategies, the synthesis strategies of isoquinoline alkaloids have been continuously optimized, and the total synthesis of these classes of natural products is reviewed critically herein. Over 250 molecules with a broad range of bioactivities, including antitumor, antibacterial, cardioprotective, anti-inflammatory, neuroprotective and other activities, are isolated and discussed. The total synthesis of more than nine classes of isoquinoline alkaloids is presented, and thirteen compounds constitute the first total synthesis. This survey provides new indications or possibilities for the discovery of new drugs from the original naturally occurring isoquinoline alkaloids.

Recent advances in oxidative dearomatization involving C-H bonds for constructing value-added oxindoles.

Exploring three-dimensional chemical space is an important research objective of organic synthetic chemistry. Oxidative dearomatization (ODA) is one of the most important and powerful tools for realizing this goal, because it changes and removes aromatic structures from aromatic compounds to increase levels of saturation and stereoisomerism by direct addition reactions between functional groups with aromatic cores under oxidative conditions. As a hot topic in indole chemistry, the synthetic value of the oxidative dearomatization of indoles has been well recognized and has witnessed rapid development recently, since it could provide convenient and unprecedented access to fabricate high-value-added three-dimensional oxindole skeletons, such as C-quaternary indolones, polycycloindolones and spiroindolones, and be widely applied to the total synthesis of these oxindole alkaloids. Therefore, this article provides a review of recent developments in oxidative dearomatization involving the C-H bonds of indoles. In this article, the features and mechanisms of different types of ODA reactions of indoles are summarized and represented, and asymmetric synthesis methods and their applications are illustrated with examples, and future development trends in this field are predicted at the end.

Recent advances in the total synthesis of polyhydroxylated alkaloids via chiral oxazines.

This review summarizes recently established methodologies developed for the enantioselective and diastereoselective synthesis of chiral 1,3-oxazines. These compounds are of interest as advanced synthetic intermediates in the total synthesis of structurally complex and biologically active polyhydroxylated alkaloids such as (+)-1-deoxynojirimycin, (-)-anisomycin, (+)-castanospermine, (+)-casuarine, (-)-conduramine F-1, (-)-sphingofungin B, Neu5Ac methyl ester, and other natural products. The devised synthetic approach aims to offer a direct, efficient, and adaptable method for obtaining both pure enantiomers and pure diastereomers. It revolves around utilizing chiral building blocks like syn,syn-, syn,syn,anti-, syn,anti-, syn,anti,syn-, anti,syn-, anti,syn,syn-, and anti,syn,anti-oxazines. By integrating oxazine chemistry with established and innovative transformations, this approach enabled the synthesis of 30 polyhydroxylated amines across various studies conducted between 2007 and 2022.

Construction of C2-indolyl-quaternary centers by branch-selective allylation: enabling concise total synthesis of the (±)-mersicarpine alkaloid.

Herein we report a branch-selective allylation strategy for accessing C2-indolyl-all-carbon quaternary centers using allylboronic acids. This approach boasts broad functional group tolerance, scalability, and relies on easily accessible allyl alcohol precursors. Importantly, the C3-position of the indole remains free, offering a handle for further synthetic refinement. Mechanistic pathways, corroborated by density functional theory (DFT), suggest the involvement of an indolenine intermediate and a Zimmerman-Traxler-like transition state during allylboration. Demonstrating its efficacy, the method was applied to the total synthesis of the (±)-mersicarpine alkaloid and enabled formal synthesis of additional alkaloids, such as (±)-scholarisine G, (±)-melodinine E, and (±)-leuconoxine.

The synthetic chemistry of sarpagine-ajmaline-type alkaloids.

The sarpagine-ajmaline type monoterpenoid indole alkaloids are among the most important groups of natural alkaloids, and the complex polycyclic and cage-like architectures present significant synthetic challenges. Because of their characteristic indole-fused azabicyclo[3.3.1]nonane structures and prominent biological activities, sarpagine-ajmaline related alkaloids have captured the attention of organic synthetic chemists for decades. In this chapter, the strategies employed in the synthesis of sarpagine-ajmaline related alkaloids are outlined, and the synthetic progress during the period of 2019-2023 is provided in detail. To provide potential targets for future synthetic endeavors, some sarpagine/ajmaline type alkaloids isolated in recent years with novel structures and biological activities are also summarized.

Huperzine alkaloids: forty years of total syntheses.

Covering: up to 2023Huperzine alkaloids are a group of natural products belonging to the Lycopodium alkaloids family. The representative member huperzine A has a unique structure and exhibits potent inhibitory activity against acetylcholine esterase (AChE). This subfamily of alkaloids provides a great opportunity for developing synthetic methodologies and asymmetric synthesis. The efforts towards the synthesis of huperzine A have cultivated dozens of total syntheses and a rich body of new chemistry. Impressive progress has also been made in the synthesis of other huperzine alkaloids. The total syntheses of huperzines B, U, O, Q and R, structure reassignment and total syntheses of huperzines K, M and N have been reported in the past decade. This review focuses on the synthetic organic chemistry and the biosynthesis and medicinal chemistry of huperzines are also covered briefly.

Total synthesis of (+)-oridamycins A and B.

We have accomplished a unified strategy to achieve the structurally intriguing indolosesquiterpene alkaloids with diverse biological activity, xiamycin A (1a), xiamycin A methyl ester (1b) and oridamycins A (2a), and B (2b), which possesses a complex 6/6/6/5/6-fused pentacyclic skeleton bearing a carbazole moiety fused with a highly functionalized trans-decalin motif. Lewis acid-mediated epoxy-ene cyclization establishes the required pentacyclic scaffold with the installation of the four contiguous stereogenic centers. Further oxidative cleavage of the vinyl functionality, followed by successive functional group interconversions, completed the total synthesis of the indolosesquiterpene alkaloids.

Enantioselective total synthesis of (+)-cylindricine B.

This article describes the first enantioselective synthesis of the Tasmanian marine alkaloid (+)-cylindricine B. The concise construction of the compound hinged on dearomative retrosynthetic logic combined with a tactical advance in the generation of congested, cyclic, alpha-tertiary amine centers. The scope of this key coupling reaction was explored in addition to providing a synthetic application for Cu-catalyzed enantioselective dearomatization of N-acyl-pyridiniums. The synthesis proceeds in five or six steps from commercially available starting materials.

Exploring the Role of Plant Carbonic Anhydrase-like Enzymes in the Synthesis of Neuroactive Alkaloids

Exploring the Role of Plant Carbonic Anhydrase-like Enzymes in the Synthesis of Neuroactive Alkaloids

A de novo synthesis of the bisindole alkaloid geissolosimine: collective synthesis of geissoschizoline, akuammicine, (16S)-deshydroxymethylstemmadenine and Aspidospermatan alkaloids

Collective synthesis of geissolosimine, geissoschizoline, akuammicine, (16S)-deshydroxymethylstemmadenine and Aspidospermatan alkaloids was achieved based on a catalytic asymmetric double Michael addition.

Four-step continuous-flow total synthesis of (-)-debromoflustramine B using a chiral heterogeneous Pd NP catalyst.

Various prenylated indoline alkaloids with diverse biological activities, including (-)-debromoflustramine B with significant butyrylcholinesterase inhibitory activity, could be synthesized by dearomative prenylation reactions of tryptophan derivatives. However, previously reported dearomative prenylations were limited to batch reactions at the milligram scale, requiring multistep reactions and complex post-processing to obtain the desired natural products. The more efficient synthesis of alkaloids remains challenging, as does the recovery of expensive catalysts. Herein, we developed a chiral heterogeneous Pd nanoparticle (NP) catalyst supported on a polymer, which produces indoline alkaloids in high yields with excellent enantioselectivities. Additionally, the first gram-scale four-step continuous-flow total synthesis of (-)-debromoflustramine B was successfully achieved with this chiral Pd heterogeneous catalyst, requiring only a simple post-processing step.