Concise Pathway Research Articles

Total Synthesis of Altemicidin: A Surprise Ending for a Monoterpene Alkaloid.

Monoterpene alkaloids encompass distinct chemical diversity and wide-ranging bioactivity. Their compact complexity has made them popular as synthetic targets and has inspired many distinct strategies and tactics in the field of heterocyclic chemistry. This article documents the evolution of a synthetic program aimed at accessing the unusual sulfonamide-containing natural product altemicidin, which was generally believed to be a monoterpene alkaloid throughout our entire synthetic investigations but has recently been found to originate through an unexpected and quite disparate biosynthetic pathway. By leveraging a pyridine dearomatization/cycloaddition strategy, we developed a concise pathway to the 5,6-fused bicyclic azaindane core and, after significant experimentation, an ultimate synthesis of altemicidin itself. Tactics to productively manipulate the multiple functional groups present on this highly polar scaffold proved challenging but were eventually realized via several carefully orchestrated and chemoselective transformations-investments that paid dividends in the form of significantly shorter chemical synthesis. Surprisingly, the bond-forming logic between our presumed abiotic synthetic strategy to this alkaloid class and its subsequently identified biosynthetic pathway is eerily similar.

A new synthetic approach to cyclic ureas through carbonylation using di-tert-butyl dicarbonate (boc anhydride) via one pot strategy.

A new approach has been successfully employed to synthesize cyclic ureas via carbonylation, utilizing Boc anhydride and employing K2CO3 as a base along with N,N-dimethylformamide as the solvent. Remarkably high yields were achieved using K2CO3 in conjunction with (Boc)2O, enabling the streamlined preparation of benzimidazolones and 2-benzoxazolones within a single reaction vessel. Significantly, this approach obviates the necessity for using any dangerous reagents, rendering it environmentally friendly, and its key benefit lies in being a metal-free system. The method stands out for its efficiency, concise pathway, optimization from readily accessible starting materials, and ease of execution. The resulting benzimidazolones and 2-benzoxazolones were thoroughly characterized using techniques including LCMS, 1H NMR, and 13C NMR.

Biosynthesis of Sordarin Revealing a Diels–Alderase for the Formation of the Norbornene Skeleton

AbstractSordarin (1) is a fungal diterpene glycoside that displays potent antifungal bioactivity through inhibition of elongation factor 2. The structures of sordarin and related compounds feature a highly rearranged tetracyclic diterpene core. In this study, we identified a concise pathway in the biosynthesis of sordarin. A diterpene cyclase (SdnA) generates the 5/8/5 cycloaraneosene framework, which is decorated by a set of P450s that catalyze a series of oxidation reactions, including hydroxylation, desaturation, and C−C bond oxidative cleavage, to give a carboxylate intermediate with a terminal alkene and a cyclopentadiene moiety. A novel Diels–Alderase SdnG catalyzes an intramolecular Diels–Alder (IMDA) reaction on this intermediate to forge the sordarin core structure. Subsequent methyl hydroxylation and glycosylation complete the biosynthesis of sordarin. Our work discloses a new strategy used by nature for the formation of the rearranged diterpene skeleton.

Biosynthesis of Sordarin Revealing a Diels-Alderase for the Formation of the Norbornene Skeleton.

Sordarin (1) is a fungal diterpene glycoside that displays potent antifungal bioactivity through inhibition of elongation factor 2. The structures of sordarin and related compounds feature a highly rearranged tetracyclic diterpene core. In this study, we identified a concise pathway in the biosynthesis of sordarin. A diterpene cyclase (SdnA) generates the 5/8/5 cycloaraneosene framework, which is decorated by a set of P450s that catalyze a series of oxidation reactions, including hydroxylation, desaturation, and C-C bond oxidative cleavage, to give a carboxylate intermediate with a terminal alkene and a cyclopentadiene moiety. A novel Diels-Alderase SdnG catalyzes an intramolecular Diels-Alder (IMDA) reaction on this intermediate to forge the sordarin core structure. Subsequent methyl hydroxylation and glycosylation complete the biosynthesis of sordarin. Our work discloses a new strategy used by nature for the formation of the rearranged diterpene skeleton.

A new configuration of composite nonlinear feedback control for nonlinear systems with input saturation

This study proposes a U-control–based Composite Nonlinear Feedback (U-CNF) design procedure. This U-CNF control establishes a double feedback loop framework for generalisation and simplification in designing the CNF control systems. Two controllers, in terms of double dynamic inversion, are designed separately, (1) to stabilise and cancel the nonlinearities and dynamics (convert the plant into an identity matrix) in the inner closed-loop, and then (2) to improve the system transient response by specifying a second-order linear system with a monotonic nonlinear function to smoothly tune the damping ratio. Accordingly, the conventional CNF characteristics in a concise pathway are achieved. The properties show, under proper conditions, the U-CNF control is plant model-free control, applicable to nonaffine nonlinear dynamic systems, and robust against model uncertainty and external disturbance. For the initial bench tests of the first-time proposed U-CNF configuration, the simulated case studies are provided with a transparent procedure to demonstrate the consistency with the analytical results in the numerical computations and to present guidance for applications.

Biotransformation of pentachlorophenol by an indigenous Bacillus cereus AOA-CPS1 isolated from wastewater effluent in Durban, South Africa.

Pentachlorophenol (PCP) is a recalcitrant biocide that bioaccumulates in the environment due to its persistent nature and has been listed as a priority pollutant due to its toxicological and health effects. In this study, a novel PCP-degrading Bacillus cereus strain AOA-CPS1 (BcAOA) was isolated from wastewater and characterized for PCP biotransformation in a batch reactor. The degradation kinetics were elucidated via substrate inhibition models, while PCP biotransformation was established by spectrophotometric and GC-MS analysis. BcAOA shared 95% sequence homology with Bacillus cereus strain XS2 and is closely related to some B. cereus strains which are previously reported to degrade PCP and other related pollutants. BcAOA degraded 74% of 350 mgl-1ofPCP within 9 days in a batch culture. The biotransformation ofPCP by BcAOA followed the first and zero-order kinetics at low and high PCP concentration, respectively, with biokinetic constants: maximum biotransformation rate (0.0996mgl-1h-1); substrate inhibition constant (723.75mgl-1); half-saturation constant (171.198mgl-1) and R2 (0.98). The genes (pcpABCDE, cytochrome P450) encoding the enzymes involved in the biodegradation of PCP were amplified from the genomic DNA of BcAOA. Further, depending upon the genes amplified and identified metabolites using GC-MS, two different PCP biotransformation pathways were proposed in this study. Cloning and expression of the catabolic genes are underway to map out the concise pathway for PCP biotransformation by BcAOA.

Asymmetric Nitrogen-Containing Dimer from Aerial Parts of Mercurialis leiocarpa and Its Synthesis by Mimicking Generation Process through Radical Intermediates.

An asymmetric nitrogen-containing dimer, leiocarpanine A, was isolated from the aerial part of Mercurialis leiocarpa as a new compound. The new generation process of leiocarpanine A was estimated and a concise synthesis of leiocarpanine A could be detailed based on mimicking the generation process through the radical intermediates. In general, a lot of reaction step and organic reagents are required for the synthesis of asymmetric nitrogen-containing dimers. However, our new synthesis method enables a concise synthesis of asymmetric nitrogen-containing dimers through radical intermediates by only liquid-separation. This synthetic method provides a rapid and concise pathway to construct a library of nitrogen-containing dimers that might be useful for drug discovery. In addition, it is useful to elucidate the generation process of leiocarpanine A.

Unprecedented [5.5.5.6]Dioxafenestrane Ring Construction in Fungal Insecticidal Sesquiterpene Biosynthesis.

Fenestranes, a specific class of natural products, contain four fused rings that share a central quaternary carbon atom. The fungal natural product penifulvin A (1) is a potent insecticidal sesquiterpene that features the [5.5.5.6]dioxafenestrane ring. Although the chemical synthesis of 1 has been achieved recently, the enzymes catalysing the cyclization and oxidation of FPP to 1 remain unknown. In this work, we identified a concise pathway that uses only three enzymes to produce 1. A new sesquiterpene cyclase (PeniA) generates the angular triquinane scaffold silphinene (6). A cytochrome P450 (PeniB) and a flavin-dependent monooxygenase (PeniC) catalyse a series of oxidation reactions to transform 6 into 1, including oxidation of the C15 methyl group to a carboxylate moiety, oxidative coupling of the C15 carboxylate and the C1-C2 olefin to form a γ-lactone, and Baeyer-Villiger oxidation to form a δ-lactone. Our results demonstrate the highly concise and efficient ways in which fungal biosynthetic pathways can generate complex sesquiterpene scaffolds.

Unprecedented [5.5.5.6]Dioxafenestrane Ring Construction in Fungal Insecticidal Sesquiterpene Biosynthesis

AbstractFenestranes, a specific class of natural products, contain four fused rings that share a central quaternary carbon atom. The fungal natural product penifulvin A (1) is a potent insecticidal sesquiterpene that features the [5.5.5.6]dioxafenestrane ring. Although the chemical synthesis of 1 has been achieved recently, the enzymes catalysing the cyclization and oxidation of FPP to 1 remain unknown. In this work, we identified a concise pathway that uses only three enzymes to produce 1. A new sesquiterpene cyclase (PeniA) generates the angular triquinane scaffold silphinene (6). A cytochrome P450 (PeniB) and a flavin‐dependent monooxygenase (PeniC) catalyse a series of oxidation reactions to transform 6 into 1, including oxidation of the C15 methyl group to a carboxylate moiety, oxidative coupling of the C15 carboxylate and the C1‐C2 olefin to form a γ‐lactone, and Baeyer–Villiger oxidation to form a δ‐lactone. Our results demonstrate the highly concise and efficient ways in which fungal biosynthetic pathways can generate complex sesquiterpene scaffolds.

Revealing the roles of components in glucose selective hydrogenation into 1,2-propanediol and ethylene glycol over Ni-MnO -ZnO catalysts

Abstract MnOx-promoted Ni-based catalyst supported by ZnO was developed to selectively hydrogenate glucose into polyols in water at 523 K with a yield of 64.9%. Using glucose, sorbitol, glycerol and LA as the raw-materials, the roles of nickel, ZnO and MnOx were investigated. The results show that nickel provided a new pathway of glucose to sorbitol and played an important role in the hydrogenation of C3 intermediates to 1,2- propanediol (1,2-PDO). The high yield of 1, 2-PDO was attributed to effective C–C bond cleavage performance of ZnO support promoted by MnOx. ZnO and MnOx contribute to the conversion of glycerol to lactic acid (LA) and LA to 1, 2-PDO, respectively. A concise pathway for hydrogenation of glucose over Ni-based catalyst was proposed.

Biosynthesis of Complex Indole Alkaloids: Elucidation of the Concise Pathway of Okaramines.

The okaramines are a class of complex indole alkaloids isolated from Penicillium and Aspergillus species. Their potent insecticidal activity arises from selectively activating glutamate-gated chloride channels (GluCls) in invertebrates, not affecting human ligand-gated anion channels. Okaramines B (1) and D (2) contain a polycyclic skeleton, including an azocine ring and an unprecedented 2-dimethyl-3-methyl-azetidine ring. Owing to their complex scaffold, okaramines have inspired many total synthesis efforts, but the enzymology of the okaramine biosynthetic pathway remains unexplored. Here, we identified and characterized the biosynthetic gene cluster (oka) of 1 and 2, then elucidated the pathway with target gene inactivation, heterologous reconstitution, and biochemical characterization. Notably, we characterized an α-ketoglutarate-dependent non-heme FeII dioxygenase that forged the azetidine ring on the okaramine skeleton.

Biosynthesis of Complex Indole Alkaloids: Elucidation of the Concise Pathway of Okaramines

AbstractThe okaramines are a class of complex indole alkaloids isolated from Penicillium and Aspergillus species. Their potent insecticidal activity arises from selectively activating glutamate‐gated chloride channels (GluCls) in invertebrates, not affecting human ligand‐gated anion channels. Okaramines B (1) and D (2) contain a polycyclic skeleton, including an azocine ring and an unprecedented 2‐dimethyl‐3‐methyl‐azetidine ring. Owing to their complex scaffold, okaramines have inspired many total synthesis efforts, but the enzymology of the okaramine biosynthetic pathway remains unexplored. Here, we identified and characterized the biosynthetic gene cluster (oka) of 1 and 2, then elucidated the pathway with target gene inactivation, heterologous reconstitution, and biochemical characterization. Notably, we characterized an α‐ketoglutarate‐dependent non‐heme FeII dioxygenase that forged the azetidine ring on the okaramine skeleton.

Biosynthesis of Strained Piperazine Alkaloids: Uncovering the Concise Pathway of Herquline A.

Nature synthesizes many strained natural products that have diverse biological activities. Uncovering these biosynthetic pathways may lead to biomimetic strategies for organic synthesis of such compounds. In this work, we elucidated the concise biosynthetic pathway of herquline A, a highly strained and reduced fungal piperazine alkaloid. The pathway builds on a nonribosomal peptide synthetase derived dityrosine piperazine intermediate. Following enzymatic reduction of the P450-cross-linked dicyclohexadienone, N-methylation of the piperazine serves as a trigger that leads to a cascade of stereoselective and nonenzymatic transformations. Computational analysis of key steps in the pathway rationalizes the observed reactivities.

γ-Lactone Synthesis via Palladium(II)-Catalyzed Lactonization of Unactivated Methylene C(sp3)–H Bonds

A palladium(II)-catalyzed intramolecular lactonization of unactivated methylene C(sp³)–H bonds using PIP bidentate auxiliary is described. This method provides an efficient and concise pathway to synthesize functionalized γ-lactones.

ChemInform Abstract: Synthesis of 2‐Aminoazoles from Thioesters via α‐Heterosubstituted Ketones by Copper‐Mediated Cross‐Coupling.

Facile synthesis of a variety of α-heterosubstituted ketones under mild conditions was achieved by copper-mediated cross-coupling of thioesters with functionalized organostannanes. Application of this coupling methodology provided a concise pathway for the conversion of carboxylic acids to 2-aminoimidazoles, 2-aminothiazoles, and 2-aminooxazoles via thioesters in practical yields.

Synthesis of 2-Aminoazoles from Thioesters via α-Heterosubstituted Ketones by Copper-Mediated Cross-Coupling.

Facile synthesis of a variety of α-heterosubstituted ketones under mild conditions was achieved by copper-mediated cross-coupling of thioesters with functionalized organostannanes. Application of this coupling methodology provided a concise pathway for the conversion of carboxylic acids to 2-aminoimidazoles, 2-aminothiazoles, and 2-aminooxazoles via thioesters in practical yields.

A concise pathway to synthesize a novel class of pyrido(2,3-d)pyrimidine-C-β-d-glycosides

A concise pathway to synthesize a novel class of nine different pyrido(2,3-d)pyrimidine-C-β-d-glycosides is reported. Formation of Michael adduct as an intermediate followed by heterocyclization are the key steps and the products were characterized by different spectral studies. β-Anomeric forms of C-glycosides were assigned from 1H NMR spectroscopy.

Concise Pathway to New Multifunctionalized Constrained Pentacin Derivatives by Means of Two Stereospecific Tandem Reactions

AbstractStarting from Boc‐activated diketopiperazines, original bicyclic derivatives of trans‐ and cis‐2‐aminocyclopentanecarboxylic acid were prepared by using two stereospecific tandem reactions. One of them is a tandem transannular rearrangement of activated lactams/alkylation process leading to the stereoselective synthesis of suitably chiral pyrrolidine‐2,4‐diones, allowing subsequent Michael‐initiated ring closure, a simple and concise route to original multifunctionalized alicyclic β‐amino esters.

Synthesis and In-vitro Antitumor Activity of 1-[3-(Indol-1-yl)prop-1-yn-1-yl]phthalazines and Related Compounds

A series of novel 3-(indol-1-yl)prop-1-yn-1-yl-substituted phthalazines and related azines was prepared via a concise pathway by palladium-catalyzed cross-coupling of appropriate halo-azines and N-propargylindoles. Some of the compounds exhibited significant antitumor activity in an in-vitro assay.

Seco-Cyclothialidines: new concise synthesis, inhibitory activity toward bacterial and human DNA topoisomerases, and antibacterial properties.

seco-Cyclothialidines are a promising class of bacterial DNA gyrase B subunit inhibitors. A new seco-cyclothialidine derivative containing a dioxazine moiety, BAY 50-7952, was synthesized through a new concise pathway. One key step of the synthesis is the straightforward formation of the 2-aminothiazole derivative of S-tritylcysteine. In biological tests, BAY 50-7952 and other known seco-cyclothialidines exhibited high and selective activity toward bacterial DNA gyrase and toward Gram-positive bacteria. The dioxazine moiety and other similar groups were found to be important for the ability of the seco-cyclothialidines to penetrate bacterial membranes. The opposite enantiomer ((S)-form) of BAY 50-7952 was also synthesized, and neither significant target activity nor in vitro antibacterial activity were found, suggesting a highly selective fit of the (R)-form. Despite promising in vitro activity, only poor activity was found in the murine infection model.