Complex Alkaloids Research Articles

Recent Advances and Perspectives in the Synthesis and Applications of Tetrahydrocarbazol‐4‐ones†

Tetrahydrocarbazol‐4‐one represents a prevalent framework of numerous natural products and pharmaceuticals. This review summaries the recent synthetic progresses of this core structure, including Fischer indolization, oxidative and reductive coupling, α‐arylative cyclization by means of transition‐ metal catalysis or under metal‐free conditions, and other methods. The recently emerged enantioselective catalytic methods of tetrahydrocarbazol‐4‐ ones are also described. The mechanistic insights and applications of these strategies as a key step in the total (formal) synthesis of complex alkaloids are highlighted as well.

The Stereoselective Nitro-Mannich Reaction in the Synthesis of Active Pharmaceutical Ingredients and Other Biologically Active Compounds.

The nitro-Mannich (aza-Henry) reaction, in which a nitroalkane and an imine react to form a β-nitroamine, is a versatile tool for target-oriented synthesis. Although the first stereoselective reaction was developed only 20 years ago, and enantioselective and diastereoselective versions for the synthesis of non-racemic compounds soon after, there are nowadays a variety of reliable methods which can be used for the synthesis of APIs and other biologically active substances. Hence many anticancer drugs, antivirals, antimicrobials, enzyme inhibitors and many more substances, containing C–N bonds, have been synthesized using this reaction. Several transition metal complexes and organocatalysts were shown to be compatible with the presence of a wide range of functional groups in these molecules, and very high levels of asymmetric induction have been achieved in some cases. The reaction has also been applied in cascade processes. The structural diversity of the products, ranging from simple heterocycles or azabicycles to complex alkaloids, iminosugars, amino acids or diamino acids and phosphonates, shows the versatility of the nitro-Mannich reaction and its potential for future developments.

The Pictet-Spengler Reaction Updates Its Habits.

The Pictet-Spengler reaction (P-S) is one of the most direct, efficient, and variable synthetic method for the construction of privileged pharmacophores such as tetrahydro-isoquinolines (THIQs), tetrahydro-β-carbolines (THBCs), and polyheterocyclic frameworks. In the lustro (five-year period) following its centenary birthday, the P-S reaction did not exit the stage but it came up again on limelight with new features. This review focuses on the interesting results achieved in this period (2011–2015), analyzing the versatility of this reaction. Classic P-S was reported in the total synthesis of complex alkaloids, in combination with chiral catalysts as well as for the generation of libraries of compounds in medicinal chemistry. The P-S has been used also in tandem reactions, with the sequences including ring closing metathesis, isomerization, Michael addition, and Gold- or Brønsted acid-catalyzed N-acyliminium cyclization. Moreover, the combination of P-S reaction with Ugi multicomponent reaction has been exploited for the construction of highly complex polycyclic architectures in few steps and high yields. The P-S reaction has also been successfully employed in solid-phase synthesis, affording products with different structures, including peptidomimetics, synthetic heterocycles, and natural compounds. Finally, the enzymatic version of P-S has been reported for biosynthesis, biotransformations, and bioconjugations.

A Concise, Enantioselective Approach for the Synthesis of Yohimbine Alkaloids.

We report a concise, enantioselective synthesis of the yohimbine alkaloids (-)-rauwolscine and (-)-alloyohimbane. The key transformation involves a highly enantio- and diastereoselective NHC-catalyzed dimerization and an amidation/N-acyliminium ion cyclization sequence to furnish four of the five requisite rings and three of the five stereocenters in two operations. This route also provides efficient access to all four diastereomeric arrangements of the core stereotriad of the yohimbine alkaloids from a common intermediate. This platform approach in combination with the ability to access both enantiomers from the carbene-catalyzed reaction is a powerful strategy that can produce a wide range of complex alkaloids and related structures for future biomedical investigations.

An Efficient Method for Synthesis of Some Novel Spirooxindole-4H-Pyran Derivatives

Oxindoles and spirooxindoles as poly-functionalized heterocycles are important synthetic targets because of their biological activity and applications to pharmaceutical guide discovery. The spirooxindole structure is usually found in a variety of complex alkaloids and many compounds that possess biological activity. In this study, we have proposed an easy and efficient access to spirooxindole from N-alkylated isatin derivatives, an activated methylene and 4-hydroxycumarin to get such compounds powerfully and suitably. Here we synthesized 18 new derivatives (4a–4r) of spirooxindoles by multicomponent reaction method. Chemical structures of all products were confirmed by IR, 1HNMR, 13CNMR, and Mass Spectroscopy. The reaction conditions were also optimized in the point of different kinds of catalysts, temperature, and solvents.

Zwitterionic Molecularly Imprinted Cross-Linked Micelles for Alkaloid Recognition in Water.

Molecular imprinting within surface/core doubly cross-linked micelles afforded water-soluble nanoparticle receptors for their template molecules. Extremely strong imprinting effects were consistently observed, with the imprinting factor >100:1 in comparison to nonimprinted nanoparticles prepared without the templates. The ionic nature of the cross-linkable surfactant strongly impacted the imprinting and binding process. Imprinted receptors prepared with a zwitterionic cross-linkable surfactant (4) outperformed a similar cationic one (1) when the template was zwitterionic or cationic and preferred their templates over structural analogues regardless of their ionic characteristics. Electrostatic interactions, however, dominated the receptors made with the cationic surfactant. The same micellar imprinting applied to simple as well as complex alkaloids. Imprinted receptors from 4 were also shown to categorize their alkaloid guests according to their structural similarity.

The Activity of Isoquinoline Alkaloids and Extracts from Chelidonium majus against Pathogenic Bacteria and Candida sp.

Chelidonium majus (Papaveraceae) extracts exhibit antimicrobial activity due to the complex alkaloid composition. The aim of the research was to evaluate the antimicrobial potential of extracts from wild plants and in vitro cultures, as well as seven major individual alkaloids. Plant material derived from different natural habitats and in vitro cultures was used for the phytochemical analysis and antimicrobial tests. The composition of alkaloids was analyzed using chromatographic techniques (HPLC with DAD detection). The results have shown that roots contained higher number and amounts of alkaloids in comparison to aerial parts. All tested plant extracts manifested antimicrobial activity, related to different chemical structures of the alkaloids. Root extract used at 31.25–62.5 mg/L strongly reduced bacterial biomass. From the seven individually tested alkaloids, chelerythrine was the most effective against P. aeruginosa (MIC at 1.9 mg/L), while sanguinarine against S. aureus (MIC at 1.9 mg/L). Strong antifungal activity was observed against C. albicans when chelerythrine, chelidonine, and aerial parts extract were used. The experiments with plant extracts, individually tested alkaloids, and variable combinations of the latter allowed for a deeper insight into the potential mechanisms affecting the activity of this group of compounds.

Second-Generation Synthesis of (+)-Fastigiatine Inspired by Conformational Studies.

(+)-Fastigiatine is a complex alkaloid isolated from the alpine club moss Lycopodium fastigatum, most commonly found in New Zealand. It has been the subject of two successful synthetic campaigns. A second-generation route toward fastigiatine was developed to resolve two problematic steps from our initial synthesis. Selective reduction and protection of the C13 ketone improved the yield and reliability of the dibromocarbene ring expansion step. In the prior synthesis, cuprate addition to the C10 enone generated a 1:1 mixture of isomers in an advanced intermediate. Protection of the C13 alcohol with a large silyl group changed the conformational preference of the enone and led to a more selective conjugate addition to produce the desired β-epimer at C10. MacMillan's decarboxylative photoredox addition method proved to be more practical than the prior aminomethyl cuprate addition chemistry. The second-generation synthesis is longer than the original but improves the selectivity and reproducibility of the overall route.

Quaternary alkaloids in Chelidonium majus in vitro cultures

Chelidonium majus L. is a medicinal plant containing several alkaloids, such as chelidonine, chelerythrine, sanguinarine, protopine, and coptisine that are stored and secreted from laticifers—highly specialized elongated cells of aerial and terrestrial parts of the plant. For use as a drug, several cultivars of this specialized crop are cultivated but the content and composition of bioactive substances is variable. Based on the observation of a characteristic orange-yellow color of latex in dedifferentiated tissue of in vitro callus cultures we investigated the alkaloid composition and the anatomy of callus and organ cultures of C. majus maintained on media enriched in plant growth regulators and illuminated with white or photosynthetically active light. Alkaloid composition was analyzed using DAD-HPLC, whereas tissue and organ anatomy was studied using light and scanning electron microscopy.The fully developed organs and rhizogenic callus compared to the undifferentiated cells, produced larger proportion of alkaloids, and complex alkaloid composition. In roots, sanguinarine was the predominant alkaloid exceeding 4 mg/g dry mass. In microshoots, coptisine was the major compound, with the maximum content exceeding 14 mg/g, depending on the medium composition. In callus cultures, either protopine or sanguinarine predominated on different media and under different illumination, with maximum content over 13 mg/g dry mass of protopine reached under PAR (Photosynthetically Active Radiation), and sanguinarine over 0.9 mg/g. The presence of laticifers was confirmed with microscopy and the scanning electron microscopy revealed an abundant extracellular matrix in the callus tissues.These results suggest the high biosynthetic potential of in vitro grown organs and dedifferentiated callus tissue that are able to produce significant amounts of pharmacologically relevant alkaloids from C. majus in various proportions that depend on the culture conditions such as supplementation with growth substances and sugars as well as on the illumination with light of different spectrum.

Development and Validation of a HPLC-ESI-MS/MS Method for Simultaneous Quantification of Fourteen Alkaloids in Mouse Plasma after Oral Administration of the Extract of Corydalis yanhusuo Tuber: Application to Pharmacokinetic Study.

The tuber of Corydalis yanhusuo is a famous traditional Chinese medicine and found to have potent pharmacological effects, such as antinociceptive, antitumor, antibacterial, anti-inflammatory, and anti-depressive activities. Although there are several methods to be developed for the analysis and detection of the bioactive ingredients’ alkaloids, so far, only few prominent alkaloids could be quantified, and in vitro and in vivo changes of comprehensive alkaloids after oral administration are still little known. In this study, we first developed a simple and sensitive high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) method to quantify the comprehensive alkaloids of extracts of C. yanhusuo in mouse plasma, using nitidine chloride as an internal standard. As results, at least fourteen alkaloids, including an aporphine (oxoglaucine), a protopine (protopine), five tertiary alkaloids (corydaline, tetrahydroberberine, tetrahydropalmatine, tetrahydrocolumbamine, and tetrahydrocoptisine) and seven quaternary alkaloids (columbamine, palmatine, berberine, epiberberine, coptisine, jatrorrhizine, and dehydrocorydaline) could be well quantified simultaneously in mouse plasma. The lower limits of quantification were greater than, or equal to, 0.67 ng/mL, and the average matrix effects ranged from 96.4% to 114.3%. The mean extraction recoveries of quality control samples were over 71.40%, and the precision and accuracy were within the acceptable limits. All the analytes were shown to be stable under different storage conditions. Then the established method was successfully applied to investigate the pharmacokinetics of these alkaloids after oral administration of the extract of Corydalis yanhusuo in mice. To the best of our knowledge, this is the first document to report the comprehensive and simultaneous analyses of alkaloids of C. yanhusuo in mouse plasma. It was efficient and useful for comprehensive pharmacokinetic and metabolomic analyses of these complex alkaloids after drug administration.

Total synthesis of complex alkaloids by nucleophilic addition to amides.

Nucleophilic addition to amides has been recognized as a promising transformation for total synthesis of complex alkaloids. Amides can accept two different organometallic reagents through the nucleophilic addition, which enables it to serve as a stable surrogate of multi-substituted amines. However, the nucleophilic addition has been overlooked for a long time due to three main reasons: low electrophilicity of amide carbonyls, potential hydrolysis of the reaction intermediate and excess addition of an organometallic reagent. This mini review focuses on the recent progress of total synthesis of complex alkaloids based on the nucleophilic additions to N-alkoxyamides, tertiary amides and secondary amides.

Strategies and Tactics for the Synthesis of Complex Alkaloids.

Efforts to achieve the laboratory synthesis of complex natural products have long served as a means to advance the science of organic chemistry. Indeed, core physical organic principles, new reagents and synthetic transformations, effective strategies for stereocontrolled synthesis, and useful pharmaceutical agents are but a few advances that have issued from such endeavors over the course of the past century. Within this review are recounted selected research programs from the author's laboratory seeking to add to that repertoire of discoveries by targeting complex polycyclic alkaloids for synthesis. Advances resulting from these studies include new strategies for the rapid synthesis of intricate molecular domains, reaction processes and sequences capable of accessing a range of diversity across several alkaloid classes, examples of achieving family-level synthetic solutions from common synthetic building blocks, and a unique perspective on effecting the laboratory synthesis of dimeric materials when direct mergers fail.

Highly Functionalized Tricyclic Oxazinanones via Pairwise Oxidative Dearomatization and N-Hydroxycarbamate Dehydrogenation: Molecular Diversity Inspired by Tetrodotoxin.

Benzenoids in principle represent attractive and abundant starting materials for the preparation of substituted cyclohexanes; however, the synthetic tools available for overcoming the considerable aromatic energies inherent to these building blocks limit the available product types. In this paper, we demonstrate access to heretofore unknown heterotricyclic structures by leveraging oxidative dearomatization of 2-hydroxymethyl phenols with concurrent N-hydroxycarbamate dehydrogenation using a common oxidant. The pairwise-generated, mutually reactive species then participate in a second stage acylnitroso Diels-Alder cycloaddition. The reaction chemistry of the derived [2.2.2]-oxazabicycles, bearing four orthogonal functional groups and three stereogenic centers, is shown to yield considerable diversity in downstream products. The methodology allows for the expeditious synthesis of a functionalized intermediate bearing structural and stereochemical features in common with the complex alkaloid tetrodotoxin.

Current Status and Future Prospects of Marine Natural Products (MNPs) as Antimicrobials.

The marine environment is a rich source of chemically diverse, biologically active natural products, and serves as an invaluable resource in the ongoing search for novel antimicrobial compounds. Recent advances in extraction and isolation techniques, and in state-of-the-art technologies involved in organic synthesis and chemical structure elucidation, have accelerated the numbers of antimicrobial molecules originating from the ocean moving into clinical trials. The chemical diversity associated with these marine-derived molecules is immense, varying from simple linear peptides and fatty acids to complex alkaloids, terpenes and polyketides, etc. Such an array of structurally distinct molecules performs functionally diverse biological activities against many pathogenic bacteria and fungi, making marine-derived natural products valuable commodities, particularly in the current age of antimicrobial resistance. In this review, we have highlighted several marine-derived natural products (and their synthetic derivatives), which have gained recognition as effective antimicrobial agents over the past five years (2012–2017). These natural products have been categorized based on their chemical structures and the structure-activity mediated relationships of some of these bioactive molecules have been discussed. Finally, we have provided an insight into how genome mining efforts are likely to expedite the discovery of novel antimicrobial compounds.

ChemInform Abstract: Quinolizidine‐Based Alkaloids: A General Catalytic, Highly Enantio‐ and Diastereoselective Synthetic Approach.

AbstractA series of quinolizidine‐based alkaloids, e.

Synthetic studies on the application of the intramolecular azide-alkene 1,3-dipolar cycloaddition reaction in the construction of the core structure of complex alkaloids

Synthesis of the core skeletons of the polycyclic alkaloids lycopodine and porantherine has been accomplished employing as a key step an Intramolecular Azide-Olefin Cycloaddition reaction (IAOC)/enamine addition/Mannich cascade reaction. Applying this methodology, the first synthesis of C15-desmethyl lycopodine has been developed.

Quinolizidine-Based Alkaloids: A General Catalytic, Highly Enantio- and Diastereoselective Synthetic Approach

Eleven quinolizidine-based alkaloids (QBAs) were synthesized in a straightforward, flexible, and stereoselective manner. As the key step, which was run on a multi-gram scale, the organocatalytic, highly enantio- and diastereoselective vinylogous Mukaiyama–Mannich reaction was used furnishing highly functionalized products carrying already two stereogenic centers. The quinolizidinone core was subsequently assembled through cyclization reactions of both ester groups with the amine moiety. Whereas the absolute configuration of the bridgehead carbon atom and the adjacent chiral center were established in the initial vinylogous Mannich reaction, the stereogenic center at the 4-position was introduced in the last step through amide activation and organometallic addition exploiting stereochemical control from the substrate. Taking advantage of this unified strategy, simple as well as more complex alkaloids were accessible in good overall yields and with high stereoselectivity. Some of the QBAs were synthesized for the first time and this study could help to assign their absolute and relative configurations.

Homodecoupled 1,1- and 1,n-ADEQUATE: Pivotal NMR Experiments for the Structure Revision of Cryptospirolepine.

Cryptospirolepine is the most structurally complex alkaloid discovered and characterized thus far from any Cryptolepis specie. Characterization of several degradants of the original, sealed NMR sample a decade after the initial report called the validity of the originally proposed structure in question. We now report the development of improved, homodecoupled variants of the 1,1- and 1,n-ADEQUATE (HD-ADEQUATE) NMR experiments; utilization of these techniques was critical to successfully resolving long-standing structural questions associated with crytospirolepine.

Total synthesis of (+)-gelsemine via an organocatalytic Diels-Alder approach.

The structurally complex alkaloid gelsemine was previously thought to have no significant biological activities, but a recent study has shown that it has potent and specific antinociception in chronic pain. While this molecule has attracted significant interests from the synthetic community, an efficient synthetic strategy is still the goal of many synthetic chemists. Here we report the asymmetric total synthesis of (+)-gelsemine, including a highly diastereoselective and enantioselective organocatalytic Diels–Alder reaction, an efficient intramolecular trans-annular aldol condensation furnishing the prolidine ring and establishing the configuration of the C20 quaternary carbon stereochemical centre. The entire gelsemine skeleton was constructed through a late-stage intramolecular SN2 substitution. The enantiomeric excess of this total synthesis is over 99%, and the overall yield is around 5%.

Total Synthesis of (±)‐8‐Oxo‐erythrinine, (±)‐8‐Oxo‐erythraline, and (±)‐Clivonine

AbstractTotal syntheses of the erythrina alkaloids (±)‐8‐oxo‐erythrinine and (±)‐8‐oxo‐erythraline have been developed, based on a substrate‐controlled intramolecular 6‐exo‐trig selective radical spirocyclization that establishes the quaternary center of the B‐rings. An improved total synthesis of (±)‐clivonine has also been reported, based on an intramolecular 6‐endo‐trig free‐radical cyclization of a highly functionalized enamide, and a biomimetic ring‐switch of a lycorine‐type intermediate. These endo/exo‐selective sequences enabled us to rapidly assemble two different complex alkaloids from a common building block in an economical fashion.