Core Of Alkaloids Research Articles

Synthesis of the ABC Core of Daphniphyllum Alkaloids with a [5-6-7] Azatricyclic Scaffold via Ring Expansion of Azabicyclic and Azatricyclic Building Blocks.

The [5-6-7] azatricyclic ABC core, found in several Daphniphyllum alkaloids, has been synthesized through a novel route involving ring expansion of a perhydroindolone to afford the AC ring system and a radical B ring closure as key steps. The level of functionalization of the reported octahydro-1,7-ethanocyclohepta[b]pyrroles suggests that they can serve as valuable building blocks in this alkaloid field. Also reported is the first synthesis of homomorphans by the ring enlargement of 2-azabicyclo[3.3.1]nonanes.

Construction of the Akuammiline Alkaloid Core Structure via Stereoselective E-Ring Formation.

Construction of the core structure of akuammiline alkaloids with three-dimensional cage-like structures for their diversity-oriented synthesis was investigated. Extensive exploration centered around the introduction of nitrogen functional groups and construction of the E-ring in an intramolecular or intermolecular manner revealed that a Claisen rearrangement approach involving intramolecular amination provided a common precursor, potentially facilitating divergent access to various types of akuammiline alkaloids.

Product Selectivity in Baeyer-Villiger Monooxygenase-Catalyzed Bacterial Alkaloid Core Structure Maturation.

Baeyer-Villiger monooxygenases (BVMOs) play crucial roles in the core-structure modification of natural products. They catalyze lactone formation by selective oxygen insertion into a carbon-carbon bond adjacent to a carbonyl group (Baeyer-Villiger oxidation, BVO). The homologous bacterial BVMOs, BraC and PxaB, thereby process bicyclic dihydroindolizinone substrates originating from a bimodular nonribosomal peptide synthetase (BraB or PxaA). While both enzymes initially catalyze the formation of oxazepine-dione intermediates following the identical mechanism, the final natural product spectrum diverges. For the pathway involving BraC, the exclusive formation of lipocyclocarbamates, the brabantamides, was reported. The pathway utilizing PxaB solely produces pyrrolizidine alkaloids, the pyrrolizixenamides. Surprisingly, replacing pxaB within the pyrrolizixenamide biosynthetic pathway by braC does not change the product spectrum to brabantamides. Factors controlling this product selectivity have remained elusive. In this study, we set out to solve this puzzle by combining the total synthesis of crucial pathway intermediates and anticipated products with in-depth functional in vitro studies on both recombinant BVMOs. This work shows that the joint oxazepine-dione intermediate initially formed by both BVMOs leads to pyrrolizixenamides upon nonenzymatic hydrolysis, decarboxylative ring contraction, and dehydration. Brabantamide biosynthesis is enzyme-controlled, with BraC efficiently transforming all the accepted substrates into its cognate final product scaffold. PxaB, in contrast, shows only considerable activity toward brabantamide formation for the substrate analog with a natural brabantamide-type side chain structure, revealing substrate-controlled product selectivity.

Regioselective Synthesis of the Tetrahydrocarbazole Core of Akuammiline Alkaloids via Palladium-Catalyzed Intramolecular Arylation Reaction.

Tetrahydrocarbazole is the central core for several biologically active alkaloids, and regioselective synthesis of this core is a challenging task. Herein, we report an efficient strategy for the synthesis of this core involving palladium-catalyzed intramolecular arylation reaction with excellent regioselectivity (>99%) starting from N-phenyl-bromoalkene without having any relocation of double bonds via competitive palladium-catalyzed isomerization reaction. Broad functional group tolerance and exclusive regioselectivity have been observed for meta-substituted halide substrates. Furthermore, this reaction can be scalable on the gram scale.

Stereoselective synthesis of fissoldhimine alkaloid analogues via sequential electrooxidation and heterodimerization of ureas.

This study develops a biogenetic synthesis strategy using electrooxidation and heterodimerization of N-substituted pyrrolidine-1-carboxamides to create diverse analogues of the fissoldhimine alkaloid core. Under acidic conditions, 2-alkoxypyrrolidine-1-carboxamides from Shono oxidation formed endo-heterodimers with high yields and diastereoselectivity. Enantioselective heterodimerization using chiral phosphoric acid catalysis produced exo-heterodimers with high enantioselectivity.

Structure, biosynthesis and activity of indolactam alkaloids.

Indolactam alkaloids are a family of aromatic toxins produced by various actinobacteria and the cyanobacterium, Moorena producens. The best characterized examples include the teleocidins, lyngbyatoxins, olivoretins, blastmycetins, and pendolmycins, which share a nine-membered lactam core, comprised from l-tryptophanol and l-valine. Contact with indolactam alkaloids has been linked to severe dermatitis (swimmers itch), while accidental ingestion may lead to illness and fatalities. Indolactam alkaloids are also potent tumor promotors, due to their activation of protein kinase C isozymes. This chapter reviews the current literature on indolactam alkaloids, from their discovery in the early 1960s up to 2024. Topics covered include the isolation, structural elucidation, biosynthesis, bioactivity, and total synthesis of the indolactam alkaloid core.

Synthesis of the 5-6-7 Tricyclic Core of Daphnicyclidin-Type Alkaloids via a Tiffeneau-Demjanov Ring Enlargement Strategy.

An expedient construction of the 5-6-7 tricyclic core of daphnicyclidin-type alkaloids is described. The synthetically challenging cycloheptanone C ring was constructed via a Tiffeneau-Demjanov ring enlargement reaction from a 5-6-6 tricyclic precursor commonly found in calyciphylline A-type alkaloids. Other key transformations included Davis oxidation, 1,2-addition, oxidation, and dehydration to elaborate the essential cyclcohept-2-enone motif.

Enantioselective Synthesis of Octahydrofuranoindole Core of Aspidosperma Alkaloids via a Diels-Alder/Reduction/Fluoroetherification Reaction Sequence.

Herein, we disclose the enantioselective synthesis of novel tricyclic fluorooctahydrofuranoindole spirooxindoles bearing five contiguous stereocenters via an organocatalytic sequential Diels-Alder/Reduction/Fluoroetherifiction reaction strategy. The potential of the developed approach was witnessed by generating vast examples (up to 20 examples) of library molecules embedding natural product core with good yields and phenomenal diastereo- and enantioselectivities (up to 77 % overall yield, up to 99 % ee and 10 : 1 dr). The synthetic utility of our protocol was further demonstrated by synthesizing tricyclic iodooctahydroindole spirooxindole framework through sequential Diels-Alder/reduction/iodoetherification reaction in 65 % overall yield and excellent stereoselectivity (99 % ee and 4 : 1 dr).

General Approach to Enantiopure 1-Aminopyrrolizidines: Application to the Asymmetric Synthesis of the Loline Alkaloids.

The synthesis of a range of loline alkaloids is reported. The C(7) and C(7a) stereogenic centers for the targets were formed by the established conjugate addition of lithium (S)-N-benzyl-N-(α-methylbenzyl)amide to tert-butyl 5-benzyloxypent-2-enoate, ensuing enolate oxidation to give an α-hydroxy-β-amino ester, and then formal exchange of the resultant amino and hydroxyl functionalities (via the intermediacy of the corresponding aziridinium ion) to give an α-amino-β-hydroxy ester. Subsequent transformation gave a 3-hydroxyprolinal derivative which was converted to the corresponding N-tert-butylsulfinylimine. Mannich-type reaction with the enolate derived from O-Boc protected methyl glycolate then formed the remaining C(1) and C(2) stereogenic centers for the targets. The 2,7-ether bridge was formed by a displacement reaction, completing construction of the loline alkaloid core. Facile manipulations then gave a range of loline alkaloids, including loline itself.

Stereoselective Mannich Reactions in the Synthesis of Enantiopure Piperidine Alkaloids and Derivatives

AbstractPiperidine alkaloids are members of the alkaloid family that is characterized by the presence of a six‐membered nitrogen‐containing heterocycle. Piperidine alkaloids are found mainly in plants and often exhibit interesting biological and pharmacological activities. Despite the accumulation of these natural products in plants, relatively low quantities of alkaloids are produced in absolute terms and thus synthesis of alkaloids and derivatives thereof remains relevant to identify targets for drug discovery. Throughout the years, researchers have come up with a myriad of methods to synthesize piperidine derivatives. This review describes methods that employ stereoselective Mannich reactions to create the core of piperidine alkaloids. Asymmetric induction in the Mannich reaction has been achieved by a range of methods that have been divided into three conceptual approaches: (1) chiral pool‐based (internal asymmetric induction), (2) chiral auxiliary‐based (relayed asymmetric induction) and (3) asymmetric catalysis‐based (external asymmetric induction). Of each approach, we describe the reaction mechanism and rationalize the stereochemical outcome of the Mannich products.

Construction of the [7–5–5] Tricyclic Core of Daphniphyllum Alkaloids via a Cationic Cascade Reaction

The [7-5-5] tricyclic core of daphniphyllum alkaloids, containing contiguous stereogenic centers at C14 and C15 and a tetrasubstituted alkene moiety between C9 and C10, was constructed via a cascade reaction that involved an electrocyclic reaction of a pentadienyl cation and intramolecular interception of the resultant cyclopentenyl cation.

Total syntheses of naturally occurring antiviral indolosesquiterpene alkaloids, xiamycins C-F via Csp3-H functionalization.

Concise total syntheses of naturally occurring antiviral indolosesquiterpene alkaloids, xiamycin C (2a), D (2b), E (2c) and F (2d), have been achieved via a late-stage oxidative δ-Csp3-H functionalization of an advanced pentacyclic enone intermediate 8. This strategy takes advantage of ipso-nitration of naturally occurring abietane diterpenoids to synthesize o-bromo nitroarene derivative 11. A Suzuki-Miyaura coupling of 11 with phenylboronic acid followed by Cadogan's ring closure provided a modular approach to a carbazole ring required for a functionalized pentacyclic core of indolosesquiterpene alkaloids.

Synthetic Studies of Daphniphyllum Alkaloids: A New Method for the Construction of [7-5-5] All-Carbon Tricyclic Skeleton

Abstract Daphniphyllum alkaloids have complex molecular structures; consequently, their synthesis can be challenging. A new method for the construction of the [7-5-5] tricyclic core of Daphniphyllum alkaloids was developed. The bicyclo[5.3.0]decane skeleton was constructed through a divinylcyclopropane rearrangement of a cyclopentenone derivative with a vinylcyclopropyl group at the β-position. After introduction of a 2-iodoethyl group by a regioselective Michael addition with phenyl vinyl selenone, the [7-5-5] tricyclic system was formed by intramolecular alkylation of a cyclopentadienyl anion species.

Total Synthesis of (-)-Kopsifoline A and (+)-Kopsifoline E.

We report the first total synthesis of (-)-kopsifoline A and (+)-kopsifoline E. Our synthetic strategy features a biogenetically inspired regioselective C17-functionalization of a versatile intermediate containing the pentacyclic core of aspidosperma alkaloids. The vinylogous urethane substructure of this intermediate affords (-)-kopsifoline D via C3-C21 bond formation under the Mitsunobu reaction conditions, while it enables selective C17-functionalization en route to (-)-kopsifoline A and (+)-kopsifoline E.

UHPLC-ESI-Orbitrap-HR-MS Analysis of Cyclopeptide Alkaloids From Ziziphus joazeiro

Ziziphus joazeiro Mart., popularly known as “juazeiro”, is a tree widely found in the northeast of Brazil. It is commonly used as an anti-inflammatory, antibacterial, antifungal, and analgesic agent. The stem extract exhibited, beside cytotoxic properties, substantial activity against the Gram-negative bacterium Allivibrio fischeri. UHPLC-ESI-Orbitrap-HR-MS analysis of the alkaloidal fraction of the crude methanolic stem extract of this species enabled the detection and putative identification of sixteen cyclopeptide alkaloids (CPAs), including four possibly new structures. According to the MS2 fragmentation analysis, from the sixteen identified CPAs, three possess a type-Ia1, one a type-Ia2, and twelve a type-Ib cyclopeptide alkaloid core. The structures of paliurine-C and -D were supported by NMR data.

A transition metal-catalyzed enyne metathesis for the preparation of pyrrolizidine alkaloid core: Application towards the total synthesis of stemaphylline

In this paper, we disclose an efficient route for the synthesis of pyrrolizidine alkaloid core and its application towards the total synthesis of stemaphylline. The key pyrrolizidine core was achieved with Ru-carbene catalyzed ring closing enyne metathesis (RCEM). The effect of different types and amounts of Ru-carbene catalysts, solvents and temperature were systematically studied. The advantage of this method includes the construction of pyrrolizidine alkaloid core in a single operation.

Construction of Protoberberine Alkaloid Core through Palladium Carbene Bridging C–H Bond Functionalization and Pyridine Dearomatization

Compounds with a pyridoisoquinolinone core often appear as members of the protoberberine alkaloid family. Traditional methods to construct this framework normally rely on manipulation of sophistica...

An approach towards the construction of the tetracyclic skeleton of palhinine alkaloids

A bifunctional Lewis acid catalyzed Diels–Alder/carbocyclization cascade process was developed for the rapid construction of the tetracyclic core of palhinine alkaloids.

Synthesis of the Madangamine Alkaloid Core by a C-C Bond Activation Cascade.

The diazatricyclic core of the madangamine alkaloids was synthesized from a densely functionalized cyclohexane derivative. An alkene and two cyanoformamide groups are used to form two new rings and a new quaternary stereocenter in a cascade reaction, which involves two Pd-catalyzed C-C bond activation steps. The synthesis of the cascade precursor involves an intramolecular Staudinger reaction of a vicinal diester that gives a [3.2.1]azabicyclooctane derivative, allowing the regioselective introduction of a monosubstituted alkene.

Synthesis of the Tricyclic Caged Core of Palhinine Alkaloids Based on a Non-Diels-Alder-Type Strategy.

A concise synthesis of the tricyclo[4.3.1.03,7]decane caged core of palhinine alkaloids was developed with SmI2-mediated cyclization and light-initiated radical addition-fragmentation as key steps. Compared with the reported racemic routes which are all based on Diels-Alder-type key reactions, our strategy would be more readily accessible to the asymmetric total syntheses of the palhinine alkaloids.