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Efficient chemical synthesis is critical to satisfying future demands for medicines, materials, and agrochemicals. Retrosynthetic analysis of modestly complex molecules has been automated over the course of decades, but the combinatorial explosion of route possibilities has challenged computer hardware and software until only recently. Here, we explore a computational strategy that merges computer-aided synthesis planning with molecular graph editing to minimize the number of synthetic steps required to produce alkaloids. Our study culminated in an enantioselective three-step synthesis of (2)-stemoamide by leveraging high-impact key steps, which could be identified in computer-generated retrosynthesis plans using graph edit distances. [ABSTRACT FROM AUTHOR]

Euptelea pleiosperma is a characteristic species of East Asian flora with both ornamental and scientific values. Based on the reduced-representation sequencing (RRS) technology of RAD-Seq, this study conducted high-throughput Illumina paired-end sequencing to find SSR marker information in the genome of E. pleiosperma, and to screen and verify polymorphism of SSR markers. We obtained 5.5G of high-quality data using RAD-Seq. The total number of contigs of the RAD tags was 299,376, with the maximum contig length of 2,062 bp and the average length of 445 bp. From these sequences, we identified 20,718 SSR loci, with a distribution density of one SSR per 6.45 kb (1/6.45 kb). Among all SSRs, dinucleotides (52.00%) were the most detected SSRs, followed by mononucleotides (21.63%). AG/CT was the dominant motif in the SSR loci, accounting for 34.8%. Primers were successfully designed for 14,593 loci, and 100 pairs of these primers were randomly selected for chemical synthesis and validated by SSR-PCR amplification in 20 individuals of E. pleiosperma. Seventy-nine primers were able to amplify the target bands. Cervus 3.0 software was used to analyze the selected 20 SSR loci with good polymorphism. For the 20 SSR markers, the number of alleles ranged from 4 to 9, and the observed heterozygosity and expected heterozygosity were from 0.35 to 0.75 and 0.541 to 0.875, respectively. The information content of polymorphic loci ranged from 0.463 to 0.848, with an average value of 0.638. Among them, there were 18 highly polymorphic loci, and 20 SSR loci did not deviate from the Hardy- Weinberg equilibrium. Furthermore, the 20 pairs of SSR primers were used to conduct PCoA analysis based on Nei's genetic distance of 51 individuals from three populations. The results showed that these SSR markers could distinguish genetic differences based on different geographical locations. [ABSTRACT FROM AUTHOR]

The development of photocascades that rapidly transform simple and readily accessible furan substrates into polycyclic alkaloid frameworks or erythrina natural products is described. Each of the sequences developed makes use of photocatalyzed energy transfer processes, which generate singlet oxygen, to set up the substrates for the second photocatalyzed reaction, wherein electron transfer generates carbon‐centered radicals for the cyclizations that give the final complex frameworks. A chemical switch has been developed that can "switch off" one photocatalyst; thus, allowing a second photocatalyst to take over control of the sequence. As a corollary, this strategy represents the first time it has been possible to use multiple photocatalysts in photocascades, and, as such, it expands significantly the reactions that can be included in such cascades and the order in which they can be initiated. [ABSTRACT FROM AUTHOR]

Over the past several decades, the 1,3-dipolar cycloaddition reaction has been successfully applied in alkaloid synthesis as a strategy to reduce the number of steps, increase overall yield and employ more easily available starting materials. This mini-review presents selected examples making use of substituted carbonyl ylides as 1,3-dipoles for the preparation of numerous nitrogenous natural products. The cycloaddition reactions of mesoionic oxazolium ylides (isomünchnones) are first discussed, wherein intramolecular reactions of these dipoles have been exploited as an approach to the ring system of several different alkaloids. The creation of carbonyl ylide dipoles from the reaction of α-diazo compounds with either ketones, esters or amides in the presence of Rh(II) catalysts has significantly broadened their applicability for natural product synthesis and is reviewed here. The cases presented demonstrate that a domino cascade strategy of these unique 'push-pull' dipoles may play a major role in shaping the future synthesis of complex nitrogen-containing natural products. [ABSTRACT FROM AUTHOR]

The diterpenoid alkaloids serve as a rich source of synthetic targets for organic chemists, due to the intriguing structure of the overlapping ring systems, along with biological activities commonly associated with compounds of this group. Fifteen total syntheses and numerous synthetic studies towards construction of ring fragments have been reported since 2010. This review article gives a brief overview of diterpenoid alkaloids and summarizes the recent synthetic efforts. 1 Introduction 1.1 Structural Classification and Biosynthetic Origin 1.2 Structure Elucidation of the Aconitum Alkaloids 2 Total Syntheses 2.1 C18-Diterpenoid Alkaloids 2.2 C19-Diterpenoid Alkaloids 2.3 C20-Diterpenoid Alkaloids 3 Strategies To Synthesize Ring Systems 3.1 Radical-Based Cyclizations 3.2 Ruthenium-Mediated Enyne Cycloisomerization 3.3 Reductive Coupling 3.4 Diels–Alder Reactions 3.5 Oxidative Dearomatization/Diels–Alder Sequence 3.6 Transannular Aziridation 3.7 Intramolecular [5+2] Cycloaddition 3.8 Miscellaneous 4 Conclusion [ABSTRACT FROM AUTHOR]

Alkylative ring-opening of bicyclic aziridinium ion generated from 4-hydroxybutylaziridine with organocopper reagent was achieved successfully to afford 2-alkylsubstituted piperidine in high or moderate yield. This method allowed carbon-carbon bond formation of “non-activated” aziridine via aziridinium ion ring-opening in regio- and stereo-selective manner for the first time. This newly developed reaction was applied for an efficient synthesis of alkaloid with the representative example of conine and epiquinamide.

Substrates are directly oxidized at the anode without using any metal catalyst and oxidant to obtain a series of nitrogen heterocyclic compounds, including benzimidazoles and quinolinones. These compounds are highly tolerant to various functional groups and heterocycle-containing substrates. In addition, natural alkaloids, such as rutaecarpine and deoxyvasicinone, can be synthesized by this method. [ABSTRACT FROM AUTHOR]

This Account describes studies carried out by my group during the past decade on both intra- and intermolecular conjugate additions of carbon nucleophiles to nitrosoalkenes. Using the Denmark protocol for the generation of nitrosoalkenes from α-chloro- O -silyloximes, a number of bridged and fused bicyclic ring systems can be prepared via the intramolecular version of this process. Intermolecular conjugate addition reactions of nitrosoalkenes with a wide variety of ester enolates as coupling partners can also be achieved efficiently using a similar procedure. Some stereochemical aspects of these nucleophilic additions have been studied with both acyclic and cyclic nitrosoalkenes. This methodology has been applied as key steps in synthetic approaches to some complex indole and Myrioneuron alkaloids. 1 Introduction 2 Conjugate Additions of Nitrosoalkenes 2.1 Background 2.2 Intramolecular Reactions 2.3 Intermolecular Reactions 2.4 Stereochemical Aspects 3 Applications to Natural Product Synthesis 3.1 Angustilodine and Related Alkaloids 3.2 Approach to Apparicine-Type Alkaloids 3.3 Myrioneurinol 4 Summary and Outlook [ABSTRACT FROM AUTHOR]

An unprecedented deoxygenative arylation of aromatic carboxylic acids has been achieved, allowing the construction of an enhanced library of unsymmetrical diaryl ketones. The synergistic photoredox catalysis and phosphoranyl radical chemistry allows for precise cleavage of a stronger C−O bond and formation of a weaker C−C bond by 1,5‐aryl migration under mild reaction conditions. This new protocol is independent of substrate redox‐potential, electronic, and substituent effects. It affords a general and promising access to 60 examples of synthetically versatile o‐amino and o‐hydroxy diaryl ketones under redox‐neutral conditions. Furthermore, it also brings one concise route to the total synthesis of quinolone alkaloid, (±)‐yaequinolone A2, and a viridicatin derivative in satisfying yields. [ABSTRACT FROM AUTHOR]

A convergent fragment‐coupling strategy for the synthesis of camptothecin is described. The key step is a photocatalytic decarboxylative radical Michael addition that attaches the ABC rings to the E ring fragment, constructing the main structure of camptothecin in five steps. This work illustrates a new strategy for the synthesis of alkaloids of the camptothecin family. [ABSTRACT FROM AUTHOR]

The present study describes a robust and general method for the synthesis of C(1)-carboxamides through IBX-mediated oxidative addition of isocyanides to tryptolines and 1,2,3,4-tetrahydroisoquinolines. In this transformation, IBX plays a dual role of an oxidant and Lewis acid to activate imine facilitating isocyanide addition. Detailed mechanistic investigations were performed by isotopic labeling and real-time NMR experiments. The method was utilized for the gram scale syntheses of two alkaloids alangiobussine and alangiobussinine in 63% and 45% overall yield, respectively. [ABSTRACT FROM AUTHOR]

An aerobic radical approach for the synthesis of unsymmetrical heteroaryl ketones is described herein. The reaction involves cross‐dehydrogenative coupling between aldehydes and heteroaromatic bases with molecular oxygen (O2). The key aspect of the method is the generation of reactive acyl radical via homolytic activation of aldehyde C−H bond using O2 as the sole oxidant. The reaction has a good substrate scope with respect to aldehydes and functionalized nitrogen heterocycles. Based on our mechanistic studies, a radical chain pathway is suggested for the reaction. A synthetic application of the method is demonstrated in the formal synthesis of natural alkaloid (±) angustureine. [ABSTRACT FROM AUTHOR]

Pyridine is a prevalent structural heterocyclic motifs in natural products, pharmaceuticals, and advanced materials. Several different methodologies have been developed for the synthesis of these kinds of molecules. However, a sustainable and efficient procedure for the synthesis of pyridines is still highly desirable. In this Synpacts article, we highlight our recent approach to the construction of highly substituted pyridines though a tandem condensation/alkyne isomerization/6π-3-azatriene electrocyclization sequence. The present protocol was used to synthesize a series of polysubstituted pyridines (30 examples) in moderate to good yields. The process also permitted the development of a concise strategy for collective total syntheses of suaveoline, norsuaveoline, and macrophylline. [ABSTRACT FROM AUTHOR]

A copper-catalyzed intramolecular α-C–H amination has been developed for the synthesis of quinazolin-4(3 H)-one derivatives from commercially available isatoic anhydride and primary and secondary benzylamines via ring-opening cyclization (ROC). This method shows good functional group tolerance and allows access to a range of 2-aryl, 2-alkyl, and spiroquinazolinone derivatives. However, 2-methylquinazolin-4(3 H)-one was synthesized from 2-amino- N -isopropylbenzamide by C–C bond cleavage, and N -benzyl-2-(methylamino)benzamide afforded 1-methyl-2-phenylquinazolin-4(1 H)-one along with 2-phenylquinazolin-4(3 H)-one by N–C bond cleavage for aromatization. It is the first general method to construct the potentially useful 2-methylquinazolin-4(3 H)-one by copper-catalyzed intramolecular C–H amination. Also this ROC strategy has been successfully applied to the synthesis of quinazolinone alkaloid rutaecarpine. [ABSTRACT FROM AUTHOR]

Several alkaloids derived from discrete Lycopodium species can treat Alzheimer's disease and increase the efficiency of learning and memory in animals. Thus, Lycopodium alkaloids bearing amazingly unique hetero‐polycyclic ring scaffolds persuaded scientists to look upon its biogenetic and biosynthetic pathways and to design its ambitious total syntheses. Recently, a C16N type Lycopodium alkaloid, (+)‐lycopladine A; isolated from the club moss Lycopodium complanatum, showed selective but modest cytotoxicity towards murine lymphoma L1210 cells (IC50 7 μg/mL). Owing to its dense array of stereochemical features, as well as intriguing biological activity, lycopladine A has been an important synthetic target for last 12 years. An overview of the synthetic studies of lycopladine A is presented, covering literature from 2006 until March 2019. [ABSTRACT FROM AUTHOR]

Reported is the enantioselective total syntheses of mavacuran alkaloids, (+)‐taberdivarine H, (+)‐16‐hydroxymethyl‐pleiocarpamine, and (+)‐16‐epi‐pleiocarpamine, and their postulated biosynthetic precursor 16‐formyl‐pleiocarpamine. This family of monoterpene indole alkaloids is a target of choice since some of its members are subunits of intricate bisindole alkaloids such as bipleiophylline. Inspired by the biosynthetic hypothesis, an oxidative coupling approach from the geissoschizine framework to form the N1−C16 bond was explored. Quaternization of the aliphatic nitrogen center was key to achieving the oxidative coupling induced by KHMDS/I2 as it masks the nucleophilicity of the aliphatic nitrogen center and locks in the required cis conformation. [ABSTRACT FROM AUTHOR]

Post-iboga alkaloids are secondary metabolites that are biosynthetically derived from iboga-type alkaloids via rearrangements of the indole and/or isoquinuclidine moieties. Herein, we categorize post-iboga alkaloids into five types based on the biosynthetic mode of transformation of the iboga scaffold. We then describe reported syntheses of post-iboga alkaloids, including our laboratory's recent contributions, based on our own categorization. 1 Introduction 1.1 Iboga and Post-Iboga Alkaloids 1.2 Classification of Post-Iboga Alkaloids 1.2.1 Introduction to Type I Post-Iboga Alkaloids 1.2.2 Introduction to Type II Post-Iboga Alkaloids 1.2.3 Introduction to Type III Post-Iboga Alkaloids 1.2.4 Introduction to Type IV Post-Iboga Alkaloids 1.2.5 Introduction to Type V Post-Iboga Alkaloids 2 Syntheses of Post-Iboga Alkaloids 2.1 Syntheses of Type I Post-Iboga Alkaloids 2.1.1 Syntheses of Monomeric Type I Post-Iboga Alkaloids 2.1.2 Syntheses of Dimeric Type I Post-Iboga Alkaloids 2.2 Syntheses of Type II Post-Iboga Alkaloids 2.3 Synthetic Studies Toward Type III Post-Iboga Alkaloids 2.4 Syntheses of Type IV Post-Iboga Alkaloids 2.5 Synthesis of Type V Post-Iboga Alkaloids 3 Conclusion and Outlook [ABSTRACT FROM AUTHOR]

Our endeavors in the design, realization and application of a formal anti -carbopalladation of alkynes are summarized. Whereas numerous examples of syn -carbopalladation steps embedded in cascade reactions are known, there have been almost no examples of the corresponding anti -carbopalladation steps. From a personal perspective, this account provides insights on the original considerations and hypotheses, and their validation or invalidation by experimental and computational means. This account also aims at clarifying how different ideas have been developed and how novel reaction sequences paving the way to a plethora of different scaffolds have been designed. The reader will recognize the importance of the interplay between elucidating reaction mechanisms and developing novel methodologies. As a result, useful methods to create homo- and heterotetrasubstituted double bonds have been developed. The broad versatility of these methods has been demonstrated by a novel total synthesis of the indole alkaloid (+)-lysergol. 1 Introduction 2 Initial Studies 3 Various Termination Steps 4 Termination with Heteronucleophiles 5 Natural Product Synthesis 6 anti -Carbopalladations Realized by the Lautens Lab 7 Conclusion and Outlook [ABSTRACT FROM AUTHOR]

An enantioselective formal synthesis of the marine alkaloid madangamine A using phenylglycinol-derived lactam 1 as the starting enantiomeric scaffold is reported. The synthesis involves the construction of the C-9 substituted diazatricyclic ABC core and the final closure of D and E rings from the polyunsaturated skipped intermediate 19. [ABSTRACT FROM AUTHOR]

Pyrroloiminoquinone alkaloids represent a structurally intriguing class of natural products that display an array of useful biological properties. Here, we present a versatile and scalable platform for the synthesis of this diverse family – and in particular the antitumor discorhabdins – built upon sequential selective C–H functionalization of tryptamine. The utility of this strategy is showcased through short formal syntheses of damirones A–C, makaluvamines D and I, and discorhadbin E. Additionally, we describe efforts to develop the first catalytic asymmetric entry to the discorhabdin subclass. Image 1 [ABSTRACT FROM AUTHOR]

Epichloë species are biotrophic symbionts of many cool-season grasses that can cause grazing animal toxicosis. We identified fungi from Hordeum brevisubulatum as Epichloë bromicola based on morphological characteristics and tefA and actG gene sequences. Three isolates were examined, they contained perA gene and 10 out of the 14 EAS cluster genes, previously identified in Epichloë inebrians E818. Five out of 11 LTM/IDT cluster genes previously identified in Epichloë festucae Fl1 were present, but no idtG, indicating an inability to produce even early intermediates in the lolitrem B pathway. Only one lolC gene out of 11 LOL cluster genes previously identified in E. festucae E2368 was present in the three isolates. Chemotype analyses revealed infected samples contained only peramine, and not ergine, ergonovine, ergovaline or lolitrem B. This study provides new information about the host range and phylogenetic definition of E. bromicola and reveal a novel endophyte-grass combination in China. [ABSTRACT FROM AUTHOR]

Starting from N-tosyltryptamine and (S)-acetoxysuccinic anhydride, a facile synthesis of (-)-indolizinoindolone has been demonstrated as a basic structural outline of bioactive subincanadine alkaloids. Regioselective Grignard reaction with (S)-acetoxysuccinimide, stereoselective intramolecular cyclization to form (-)-indolizinoindolone skeleton and TiCl4 induced condensation with acetaldehyde for stereoselective generation of exocyclic carbon-carbon double bond are the key features. [ABSTRACT FROM AUTHOR]

• First reported synthesis of trigonostemine A and trigonostemine B. • New synthesis of pityriacitrin and hyrtiosulawesine. • An improved preparation of 1-formyl-β-carboline building blocks. The total synthesis of four natural products, trigonostemine A, trigonostemine B, pityriacitrin, and hyrtiosulawesine was accomplished. The key intermediates, variously substituted 1-formyl-β-carbolines, were prepared in five steps via a novel synthetic approach using readily available starting materials. These formyl derivatives were then further transformed, providing a general route for the synthesis of the four title alkaloids. The method reported herein represents the first total synthesis of the two trigonostemines and a new pathway to pityriacitrin and hyrtiosulawesine. [ABSTRACT FROM AUTHOR]

Cadogan reductive cyclization of substituted 2-aryl-3-nitropyridines to give δ-carbolines was performed under MoO2 Cl2 (DMF)2 catalysis with triphenylphosphine as a ligand. A new approach for the synthesis of the alkaloid quindoline based on a Mo(VI)-catalyzed Cadogan reductive cyclization of 2-phenyl-3-nitro-5,6,7,8-tetrahydroquinoline followed by aromatization of the resulting 2,3,4,10-tetrahydro-1 H -indolo[3,2- b ]quinoline is proposed. Various о -nitroarylpyridines, obtained by reacting acylpyruvates and cyclic hydroxymethylene ketones with nitroacetophenone enamines, were used as starting compounds for the preparation of δ-carbolines. The synthesized δ-carbolines were found to act as phosphors; their photophysical properties were studied and a structure–property relationship was revealed. [ABSTRACT FROM AUTHOR]

A series of N -phenethylcinnamamides were subjected to the Bischler–Napieralski reaction to furnish diverse 1-styryl-3,4-dihydroisoquinolines. We noticed that the desired products were unstable when the reaction was performed under conventional solvent conditions. However, when [bmim]PF6 was used as the reaction media, the nature of the Bischler–Napieralski reaction promoted an unusual in situ ionic interchange between this ionic liquid and the dihydroisoquinoline core that led to the stabilization of the desired 1-styryl-3,4-dihydroisoquinolines, allowing their isolation as hexafluorophosphate salts. Finally, the one-pot reduction/reductive methylation process afforded the N -methyl derivatives, establishing that our findings can be an efficient and useful strategy for the concise synthesis of tetrahydroisoquinoline alkaloids. [ABSTRACT FROM AUTHOR]

Strictamine and rhazinoline are representative methanoquinolizidine‐containing akuammiline alkaloids that possess different stereochemistry at the C16 position. A unified approach to the enantioselective total syntheses of these two molecules is described. The key steps in this synthesis include a photocatalytic intra/intermolecular type II radical cascade reaction, a Tsuji–Trost allylation, a palladium‐ or nickel‐mediated cyclization, and a late‐stage intramolecular N‐alkylation reaction. Unified syntheses of the challenging methanoquinolizidine‐containing akuammiline alkaloids (−)‐strictamine and (−)‐rhazinoline have been achieved in an enantioselective fashion employing photocatalytic cascade and transition‐metal‐mediated cyclization reactions as key steps. [ABSTRACT FROM AUTHOR]

A concise and highly stereoselective total synthesis of the Daphniphyllum alkaloids (−)‐daphenylline has been accomplished. The synthesis was started from (S)‐carvone and proceeded via a stereoselective Mg(ClO4)2‐catalyzed intramolecular amide addition cyclization, an intramolecular Diels–Alder reaction to construct the ABCD tetracyclic core architecture, and a Robinson annulation coupled with an oxidative aromatization sequence. Finally, the DF ring system was installed through an intramolecular Friedel–Crafts cyclization. The total synthesis of (−)‐daphenylline is achieved in 19 steps in the longest reaction sequence and in 7.6 % overall yield. Round, round, get around: A concise and highly enantioselective total synthesis of (−)‐daphenylline was accomplished in 19 steps and 7.6 % overall yield from (S)‐carvone. It features an Mg(ClO4)2‐catalyzed intramolecular amide cyclization and a Diels–Alder cycloadditon to construct the tetracyclic motif, a tandem Robinson annulation with oxidative aromatization, and an intramolecular Friedel–Crafts acylation and Nazarov‐type cyclization to construct the DF rings. [ABSTRACT FROM AUTHOR]

Appending functional groups to the core skeleton of natural α‐noscapine, an FDA approved cough medicine, resulted in analogues with anticancer activity. In this study, we report the synthesis and antiproliferative activity of 9‐formyl and 9‐ethynylnoscapines. 9‐Formylnoscapine 5 was synthesized from 9‐bromonoscapine 2cvia a three‐step reaction sequence involving palladium catalysed Heck reaction with ethyl acrylate leading to noscapinoid 7, dihydroxylation of 7 with OsO4 and oxidative cleavage of diol 8. Further, Seyferth‐Gilbert homologation of 9‐formylnoscapine using Bestmann‐Ohira reagent resulted in 9‐ethynylnoscapine 6 in excellent yield. Antiproliferative activity screening of new noscapinoids 5‐7 against NCI60 human tumor cell lines resulted in 9‐ethynylnoscapine 6 as a potent anticancer agent with the lowest mean percentage growth against the full 60‐cell line panel. [ABSTRACT FROM AUTHOR]

Various (activated and non-activated) aziridines with diverse substitution patterns have been deployed successfully as starting materials for the synthesis of a wide variety of alkaloids via suitable functionalization and aziridine ring transformation. Alternatively, the preparation and interception of reactive aziridine intermediates has also been shown to constitute a valid approach toward alkaloid synthesis. This review summarizes aziridine-mediated syntheses of alkaloids, in which the aziridine is mobilized as either a substrate or an advanced synthetic intermediate. 1 Introduction 2 Alkaloids Synthesis from Aziridine Starting Materials 2.1 (2 R)- and (2 S)-Hydroxymethyl- N -(1-phenylethyl)aziridines 2.2 N -Benzylaziridine-2-carboxylates 2.3 2-Substituted N -Tosyl- or N -Tritylaziridines 2.4 2,3-Disubstituted N -Cbz- or N -Tosylaziridines 2.5 N -DMB-aziridines 3 Alkaloids Synthesis from Aziridines as Key Advanced Synthetic Intermediates 3.1 Alkylative Aziridine Ring Opening 3.2 Arylative Aziridine Ring Opening 3.3 Ring Expansion 3.4 Oxidative Aziridine Ring Opening 3.5 Heteroatomic Nucleophilic Aziridine Ring Opening 3.6 Reductive Aziridine Ring Opening 4 Conclusion [ABSTRACT FROM AUTHOR]

A unified strategy enabled the enantioselective syntheses of (−)-scholarisine G, (+)-melodinine E, (−)-leuconoxine and (−)-mersicarpine from a common 2-alkylated indole intermediate bearing an all-carbon quaternary stereogenic center. The Smith-modified Madelung indole synthesis was used to couple simple o-toluidine with chiral lactone (+)-8, incorporating the key elements for further cyclizations. Lactone (+)-8 was prepared via a palladium-catalyzed intermolecular asymmetric allylic alkylation. The unified and protecting-group-free reaction sequences allowed the synthesis of these alkaloids in a maximum of 10 steps and with high efficiency. [ABSTRACT FROM AUTHOR]

Abstract Attempts to the construction of B/C ring and E ring in melotenine A are described. Based on para -dienone chemistry, a tactical application of tandem aminolysis/aza-Michael addition reaction was made to access highly functionalized building blocks with the pyrrolo[2,3- d ]carbazole tetracyclic unit (A/B/C/D ring). Albeit negative results for assembling the dihydroazepine unit (E ring) by using the proposed fragmentation reaction of gem -dihalocyclopropanes, an alternative strategy based on ring closing metathesis was evolved to forge the E ring possessing a twisted 1,3-diene unit embedded in the rigid skeleton of melotenine A. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

Cyclodipeptide 2,5‐diketopiperazines (DKP) are privileged structural units present in drugs and natural alkaloids. This work reports a new method for the synthesis of biologically important DKP scaffolds based on an intramolecular nucleophilic α‐addition of general amides towards an alkynamide system. The utility of this umpolung cyclization mediated by trimethyl phosphine and l‐glutamic acid is highlighted by its application to the concise total syntheses of 6‐methoxyspirotryprostatin B (the first total synthesis), spirotryprostatin A, and spirotryprostatin B. Alkaloid synthesis: This work reports a concise and practical approach towards the synthesis of spirotryprostatins. This synthetic route features an organo‐mediated intramolecular umplolung cyclization to construct the DKP ring system, a Grignard addition‐dehydration‐Friedel–Crafts reaction procedure to establish the C‐ring and the prenyl moiety, and a regioselective oxidation and microwave‐assisted stereospecific rearrangement to afford the spiro‐oxindole system. [ABSTRACT FROM AUTHOR]

Abstract The tetrahydro-β-carboline (THBC) nucleus is a predominant feature of a vast array of naturally occurring alkaloids. Most of these alkaloids have been found to exhibit significant biological activities, which promote to develop a plethora of synthetic methods for the construction of THBCs. In this review, we focus on the recent developments and studies related to the synthesis of THBCs including total syntheses of related alkaloids mainly over the period of 2000–2017. In addition, a brief account of some significant THBC alkaloids with their sources and bioactivities is also presented in tabular format. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

This work describes the total synthesis of three members of the sarpagine alkaloid family and ten non‐natural congeners through an improved synthetic sequence, which was designed for gram‐scale production of materials suited for structure–activity relationship (SAR) studies. Furthermore, the manuscript details how the synthetic route was used to access the biogenetically completely unrelated Stemona alkaloid parvineostemonine (34), providing a showcase for efficient synthetic design. A generalized total synthesis for Stemona and sarpagine alkaloids was achieved (see graphic). The common privileged intermediate was accessed via a [5+2]‐cycloaddition reaction in six steps. Both alkaloid families were synthesized in a total of 11 and 12 steps, respectively, of which they shared six steps in total. [ABSTRACT FROM AUTHOR]

A quantitative synthesis of piperine from commercially available starting material is presented. The synthesis relies on a stereoselective nucleophilic attack of an in situ generated cuprate onto a cyclobutene lactone. The so-formed aryl-substituted cyclobutene spontaneously undergoes a conrotatory 4π-electrocyclic ring opening to form the 4-aryl pentadienoic acid as a single diastereoisomer. The high-yielding synthesis can be easily modulated on the aryl and on the amide moiety for the synthesis of a wide range of piperine analogues. [ABSTRACT FROM AUTHOR]

Abstract A Suzuki-Miyaura cross coupling, followed by triphenylphosphine mediated Cadogan reductive cyclization sequence provided efficient access to a series of carbazole alkaloids. In the present work, this approach was applied to the total synthesis of mukonine, clauszoline K, koenoline, murrayanine, murrayafoline A, mukoeic acid, glycoborine, glycozolicine, mukolidine, mukoline, glycozoline, 3-methoxy-9 H -carbazole-1-carboxylic acid methyl ester, (3-methoxy-9 H -carbazol-1-yl)-methanol, 3-methoxy-9 H -carbazole-1-carbaldehyde, 3-methoxy-9 H -carbazole-1-carboxylic acid, 2-methyl-9 H -carbazole and nonsteroidal anti-inflammatory drug (NSAID) carprofen and its derivatives. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

We designed and synthesized cinchona alkaloid derivates PMI-BnCPD, 1 and PMI-dHQD, 2, in which a fluorescent perylene monoimide unit is linked to the quinuclidine fragment. The latter acts as an electron donor, quenching the perylene imide fluorescence in polar solvents. In the organocatalytic application of these compounds, the electron donor is deactivated by binding to an electrophile, e.g. H+. We show that this restores the fluorescence, allowing the compounds to signal the electrophile binding step that occurs in many catalytic reactions. In order to demonstrate that charge transfer is indeed the fluorescence quenching mechanism, we detected the charge separated state by means of transient absorption spectroscopy. Incidentally, the excited state absorption bands of the locally excited and charge transfer states are very similar. The activity of the fluorophore labeled organocatalyst 1 in a fluorogenic Michael addition reaction is demonstrated. [ABSTRACT FROM AUTHOR]

Crosslinked chiral polysiloxanes containing cinchona alkaloid derivatives were synthesized from poly(methylhydrosiloxane) by hydrosilylation reaction. The C3‐vinyl group of cinchona alkaloid derivatives were easily hydrosilylated with Si−H functional groups of poly(methylhydrosiloxane) by using Pt catalyst. The reaction between cinchona alkaloid dimers and poly(methylhydrosiloxane) and afforded the crosslinked chiral polysiloxanes. Partial hydrolysis of Si−H bonds with Pt catalyst during reaction resulted in a formation of extra crosslinkages of chiral polysiloxanes. Mixed solvent (toluene and DMF) system was employed for a successful immobilization of C6′−OH free cinchona alkaloid derivatives into poly(methylhydrosiloxane). Both cinchona alkaloid C9‐ester and C9‐urethane derivatives were incorporated into poly(methylhydrosiloxane) through Si−C bond. The resulted crosslinked chiral polysiloxanes were insoluble in common organic solvents. Their catalytic performance was evaluated in asymmetric Michael addition reactions. The chiral polysiloxanes of cinchona alkaloid having C6′−OH showed higher enantioselectivities (up to 99% ee) with sufficient catalytic activities in the Michael addition reactions. The chiral polysiloxanes were easily recovered by filtration or centrifugation method and could be reused for several times without losing their catalytic performance. Crosslinked polysiloxanes of cinchona alkaloid derivatives acted as efficient catalysts for the enantioselective Michael addition of β‐ketoesters with nitroolefins to give chiral products in good yields with excellent stereoselectivities (up to 99% ee, 4.5 : 1 d.r.). [ABSTRACT FROM AUTHOR]

A general and efficient protocol was developed for the synthesis of polysubstituted pyridines from propargyl amines and unsaturated carbonyl compounds through a tandem condensation/alkyne isomerization/6π 3‐azatriene electrocyclization sequence. This process was found to be applicable to a wide range of readily available substrates (30 examples, up to 95 % yield) and could be readily performed on a preparative (20 g) scale. By taking advantage of this method for late‐stage pyridine incorporation, we successfully completed the collective total synthesis of suveoline, norsuveoline, and macrophylline. [ABSTRACT FROM AUTHOR]

A scalable enantioselective total synthesis of (−)‐goniomitine has been developed by using an iridium‐catalyzed asymmetric hydrogenation of an exocyclic enone ester to control the configuration of the molecule. The synthesis begins from commercially available starting materials, and proceeds through an integrated asymmetric ketone hydrogenation, Johnson–Claisen rearrangement, and one‐pot oxidation/deprotection/cyclization process. With this highly efficient and scalable strategy, (−)‐goniomitine was synthesized in eleven steps with 27 % overall yield, and formal enantioselective syntheses of (+)‐1,2‐dehydroaspidospermidine, (+)‐aspidospermidine, and (+)‐vincadifformine were also achieved. Going, going, goniomitine: A scalable enantioselective synthetic strategy featuring an iridium‐catalyzed asymmetric hydrogenation of an exocyclic enone ester for the total synthesis of (−)‐goniomitine and formal syntheses of (+)‐1,2‐dehydroaspidospermidine, (+)‐aspidospermidine, and (+)‐vincadifformine is reported. [ABSTRACT FROM AUTHOR]

Abstract Inspired by the simple and attractive structure of zanthoxylamide protoalkaloids: armatamide, rubecenamide, lemairamin, rubemamine and zanthosine; isolated from plants of the genus Zanthoxylum. We report the synthesis of a series of 29 substituted N -phenylethyl cinnamamides through the direct amidation of a variety of cinnamic acids with a broad range of phenylethylamines promoted by tris -(2,2,2-trifluoroethyl) borate (B(OCH 2 CF 3) 3) in excellent yields and under mild reaction conditions. Then, the toxicological profile of the prepared compounds was studied through in silico computational methods, analyzing eight toxicity risks (hepatotoxicity, mutagenic, carcinogenicity, tumorigenic, immunotoxicity, cytotoxicity, irritant and reproductive effects) and two toxicity targets (AOFA and PGH1), while the acute toxicity toward zebrafish embryos (96 hpf-LC 50 , 50% lethal concentration) was also determined in the present study. From the results of the toxicity tests, we concluded that zanthoxylamide protoalkaloids can be classified as slightly toxic compounds, with a LC 50 values around 217 μM that gave an understanding of their toxicity on living organisms and their possible environmental impact. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

This Minireview is focused on an in‐depth discussion of comparative strategies to construct the gelsemine and gelsedine classes of the gelsemium alkaloids. This document highlights the diversity of strategies used to access specific motifs found within these targets: a) the fused "[3.2.1]bicycle" (in gelsemine) and "oxabicycle" (in gelsedine class); b) the "piroxindole" moiety with C7 quaternary center; c) the "N‐heterocycles" and d) the "THP" moiety with C20 quaternary center (in gelsemine). [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • The shortest-step asymmetric total synthesis of lycopodine was accomplished. • The first asymmetric synthesis of flabelliformine was achieved. • The strategy includes a novel cascade cyclization to construct tetracyclic structure. Abstract The shortest asymmetric total synthesis of lycopodine (3) and the first asymmetric total synthesis of flabelliformine (4) were accomplished by a strategy that features a cascade cyclization of linear substrate (5) to construct tetracyclic structure (6). [ABSTRACT FROM AUTHOR]

Background: Dendrobium huoshanense C.Z. Tang et S.J. Cheng is a traditional Chinese herbal medicine with high medicinal value in China. Polysaccharides and alkaloids are its main active ingredients. To understand the difference of main active ingredients in different tissues, we determined the contents of polysaccharides and alkaloids in the roots, stems and leaves of D. huoshanense. In order to explore the reasons for the differences of active ingredients at the level of transcription, we selected roots, stems and leaves of D. huoshanenese for transcriptome sequencing and pathway mining. Results: The contents of polysaccharides and alkaloids of D. huoshanense were determined and it was found that there were significant differences in different tissues. A total of 716,634,006 clean reads were obtained and 478,361 unigenes were assembled by the Illumina platform sequencing. We identified 1407 carbohydrate-active related unigenes against CAZy database including 447 glycosyltransferase genes (GTs), 818 glycoside hydrolases (GHs), 60 carbohydrate esterases (CEs), 62 carbohydrate-binding modules (CBMs), and 20 polysaccharide lyases (PLs). In the glycosyltransferases (GTs) family, 315 differential expression genes (DEGs) were identified. In total, 124 and 58 DEGs were associated with the biosynthesis of alkaloids in Dh_L vs. Dh_S and Dh_R vs. Dh_L, respectively. A total of 62 DEGs associated with the terpenoid pathway were identified between Dh_R and Dh_S. Five key enzyme genes involved in the terpenoids pathway were identified, and their expression patterns in different tissues was validated using quantitative real-time PCR. Conclusions: In summary, our study presents a transcriptome profile of D. huoshanense. These data contribute to our deeper relevant researches on active ingredients and provide useful insights into the molecular mechanisms regulating polysaccharides and alkaloids in Dendrobium. [ABSTRACT FROM AUTHOR]

First total synthesis of a rare β‐carboline–vasicinone hybrid alkaloid (±)‐peharmaline A has been accomplished in just 3 steps starting from known compounds. Stereoselective Pictet–Spengler reaction to nitrogenated tertiary carbon center and one‐pot construction of the tricyclic skeleton of vasicinone are the highlights of present synthesis. We have also synthesized structurally close analogues of the natural product by following the developed route. The first total synthesis of the anticancer natural product (±)‐peharmaline A was accomplished in three steps. A stereoselective Pictet–Spengler reaction followed by the construction of the vasicinone moiety in a one‐pot fashion are the highlights. The developed route is useful to access peharmaline analogues, which opens opportunities for systematic structure–activity relationship studies during biological evaluation. [ABSTRACT FROM AUTHOR]

Background: Nuciferine, a major bioactive component from the lotus leaf, has been reported to have notable anti-inflammatory activities such as renal inflammation and acute lung injury in previous studies. Mastitis is one of the most prevalent diseases in the dairy cattle, which causes large economic losses for the dairy industry. However, the effects of nuciferine on lipopolysaccharide (LPS)-induced mastitis have not been reported.Methods and results: Here, we investigated the anti-inflammatory effects of nuciferine on LPS-induced mastitis in mice and illuminated its potential mechanism on the TLR4-mediated signaling pathway in mouse mammary epithelial cells (mMECs). Histopathological changes and myeloperoxidase (MPO) activity assay showed that nuciferine treatment significantly alleviated the LPS-induced injury of mammary gland flocculus, inflammatory cells infiltration. qPCR and ELISA assays indicated that nuciferine dose-dependently reduced the levels of TNF-α and IL-1β, which indicated that nuciferine might have therapeutic effects on mastitis. Furthermore, nuciferine treatment significantly decreased the expression of TLR4 in a dose-dependent manner. Besides, nuciferine was also found to suppress LPS-induced NF-κB activation.Conclusion: These findings indicate that nuciferine potently ameliorates LPS-induced mastitis by inhibition of the TLR4-NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Nicotiana rustica (Aztec tobacco), like common tobacco (Nicotiana tabacum), is an allotetraploid formed through a recent hybridization event; however, it originated from completely different progenitor species. Here, we report the comparative genome analysis of wild type N. rustica (5 Gb; 2n = 4x = 48) with its three putative diploid progenitors (2.3–3 Gb; 2n = 2x =24), Nicotiana undulata, Nicotiana paniculata and Nicotiana knightiana. Results: In total, 41% of N. rustica genome originated from the paternal donor (N. undulata), while 59% originated from the maternal donor (N. paniculata/N. knightiana). Chloroplast genome and gene analyses indicated that N. knightiana is more closely related to N. rustica than N. paniculata. Gene clustering revealed 14,623 ortholog groups common to other Nicotiana species and 207 unique to N. rustica. Genome sequence analysis indicated that N. knightiana is more closely related to N. rustica than N. paniculata, and that the higher nicotine content of N. rustica leaves is the result of the progenitor genomes combination and of a more active transport of nicotine to the shoot. Conclusions: The availability of four new Nicotiana genome sequences provide insights into how speciation impacts plant metabolism, and in particular alkaloid transport and accumulation, and will contribute to better understanding the evolution of Nicotiana species. [ABSTRACT FROM AUTHOR]

Traditional methods of chemical synthesis of alkaloids exhibit various problems such as lack of enantioselectivity, the use of toxic chemical and intermediates, and multiple numbers of synthetic steps. Consequently, various enzymatic methods for the formation of C−C bonds in the alkaloid skeleton have been developed. Herein, we report advances achieved in the enzymatic or chemo‐enzymatic synthesis of pharmaceutically important alkaloids that employ three C−C bond forming enzymes: two Pictet‐Spenglerases and the oxidative C−C bond forming flavoenzyme Berberine Bridge Enzyme. Protein engineering studies, improving the substrate scope of these enzymes, and thereby leading to the synthesis of non‐natural alkaloids possessing higher or newer pharmacological activities, are also discussed. Furthermore, the integration of these biocatalysts with other enzymes, in multi‐enzymatic cascades for the enantioselective synthesis of alkaloids, is also reviewed. Current results suggest that these enzymes hold great promise for the generation of C−C bonds in the selective synthesis of alkaloid compounds possessing diverse pharmacological properties. Enzymes for alkaloids: This review provides a comprehensive account of three important C−C bond forming enzymes, the Pictet‐Spenglerases Strictosidine synthase (STR) and Norcoclaurine synthase (NCS), and the oxidative C−C bond forming flavoenzyme Berberine Bridge Enzyme (BBE). Advances achieved in the enzymatic and chemo‐enzymatic synthesis of pharmaceutically important alkaloids are discussed. [ABSTRACT FROM AUTHOR]