Acyclic Precursors Research Articles

Aziridine Group Transfer via Transient N-Aziridinyl Radicals.

Aziridines are the smallest nitrogen-containing heterocycles. Strain-enhanced electrophilicity renders aziridines useful synthetic intermediates and gives rise to biological activity. Classical aziridine syntheses─based on either [2 + 1] cycloadditions or intramolecular substitution chemistry─assemble aziridines from acyclic precursors. Here, we introduce N-aziridinyl radicals as a reactive intermediate that enables the transfer of intact aziridine fragments in organic synthesis. Transient N-aziridinyl radicals are generated by the reductive activation of N-pyridinium aziridines and are directly characterized by spin-trapped EPR spectroscopy. In the presence of O2, N-aziridinyl radicals are added to styrenyl olefins to afford 1,2-hydroxyaziridination products. These results establish aziridinyl radicals as new reactive intermediates in synthetic chemistry and demonstrate aziridine group transfer as a viable synthetic disconnection.

Assembly of 2-Substituted Tetrahydroquinolines from ortho-Methylbenzenesulfamides and Dienes, Using a C(sp3)-H Activation/Annulation Sequence.

1,2,3,4-Tetrahydroquinolines (THQs) are essential structural cores in many natural products and pharmaceutical drugs. Especially relevant are those presenting substitutions at position 2, yet practical methods for their one-step assembly from acyclic precursors are very scarce. Herein, we present a straightforward approach to assembling these skeletons from ortho-methylanilines using a palladium-catalyzed C(sp3)-H activation/formal cycloaddition sequence. Key for the success of the approach is the use of dienes as partners, since they lead to stable π-allyl palladium intermediates that prevent β-hydride elimination processes and allow installation of versatile alkenyl handles at position 2. Moreover, installing a perfluorobenzenesulfonyl substituent at the amine not only facilitates the C-H activation but also allows for an easy recovery of the free amine.

Synthesis of Bridged Five-Membered Ring Systems by Type II [3 + 2] Annulation of Allenylsilane-ene.

The first type II intramolecular [3 + 2] annulation of allenylsilane-ene has been achieved, enabling diastereoselective and efficient construction of synthetically challenging bridged five-membered ring systems such as bicyclo[3.2.1]. This mild and direct process shows a broad substrate scope and is highly stereospecific. Particularly, this work represents the first stereoselective method for the direct synthesis of bicyclo[3.2.1] ring systems from acyclic precursors. Additionally, the first asymmetric total syntheses of (+)- and (-)-strepsesquitriol, and the efficient formation of the synthetically challenging tetracyclic core of pierisjaponol D are achieved by this type II [3 + 2] annulation reaction.

One-step syntheses of diaza-dioxa-fenestranes via the sequential (3 + 2) cycloadditions of linear precursors and their structural analyses

Fenestranes, in which four rings share one carbon atom, have garnered much attention because of their flattened quaternary carbon centers. In addition, the rigid and nonplanar structures of heteroatom-containing fenestranes are attractive scaffolds for pharmaceutical applications. We report one-step syntheses of diaza-dioxa-fenestranes via the sequential (3 + 2) cycloadditions. Our synthesis employs readily synthesizable, nonbranched acyclic allenyl precursors that facilitate sequential cycloaddition reactions. We report the synthesis of 22 heteroatom-containing and differently substituted fenestranes with rings of varying sizes. The prepared diaza-dioxa-fenestranes are subjected to X-ray crystallography and DFT calculations, which suggest that replacing the carbon atoms at the non-bridgehead positions in the fenestrane skeleton with nitrogen and oxygen atoms results in a slight flattening of the quaternary carbon center. Moreover, one of our synthesized c,c-[5.5.5.5]fenestranes containing two isoxazoline rings possesses the flattest quaternary carbon center among previously synthesized heteroatom-containing fenestrane versions.

Synthesis of Aza[n]helicenes up to n = 19: Hydrogen-Bond-Assisted Solubility and Benzannulation Strategy.

Synthetic challenges toward anomalous structures and electronic states often involve handling problems such as insolubility in common organic solvents and oxidative degradation under aerobic conditions. We designed benzo-annulated aza[n]helicenes, which benefit from both the suppressed elevation of highest occupied molecular orbital (HOMO) energies and high solubility due to hydrogen bonding with solvent molecules to overcome these challenges. This strategy enabled the synthesis of six new aza[n]helicenes ([n]AHs) of different lengths (n = 9-19) from acyclic precursors via one-pot intramolecular oxidative fusion reactions. The structures of all of the synthesized aza[n]helicenes were determined by X-ray diffraction (XRD) analysis, and their electrochemical potentials were measured by cyclic voltammetry. Among the synthesized aza[n]helicenes, [17]AH and [19]AH are the first heterohelicenes with a triple-layered helix. The noncovalent interaction (NCI) plots confirm the existence of an effective π-π interaction between the layers. The absorption and fluorescence spectra red-shifted as the helical lengths increased, without any distinct saturation points. The optical resolutions of N-butylated [9]AH, [11]AH, [13]AH, and [15]AH were accomplished, and their circular dichroism (CD) and circularly polarized luminescence (CPL) were measured. Thus, the structural, (chir)optical, and electrochemical properties of the aza[n]helicenes were comprehensively analyzed.

Discovery of macrocyclic CDK2/4/6 inhibitors with improved potency and DMPK properties through a highly efficient macrocyclic drug design platform

Cyclin-dependent kinases (CDKs) are critical cell cycle regulators that are often overexpressed in tumors, making them promising targets for anti-cancer therapies. Despite substantial advancements in optimizing the selectivity and drug-like properties of CDK inhibitors, safety of multi-target inhibitors remains a significant challenge. Macrocyclization is a promising drug discovery strategy to improve the pharmacological properties of existing compounds. Here we report the development of a macrocyclization platform that enabled the highly efficient discovery of a novel, macrocyclic CDK2/4/6 inhibitor from an acyclic precursor (NUV422). Using dihedral angle scan and structure-based, computer-aided drug design to select an optimal ring-closing site and linker length for the macrocycle, we identified compound 8 as a potent new CDK2/4/6 inhibitor with optimized cellular potency and safety profile compared to NUV422. Our platform leverages both experimentally-solved as well as generative chemistry-derived macrocyclic structures and can be deployed to streamline the design of macrocyclic new drugs from acyclic starting compounds, yielding macrocyclic compounds with enhanced potency and improved drug-like properties.

Continuous Flow Synthesis of Benzotriazin-4(3H)-ones via Visible Light Mediated Nitrogen-Centered Norrish Reaction.

We report a new protocol for the synthesis of substituted benzotriazin-4(3H)-ones which are underrepresented heterocyclic scaffolds with important pharmacological properties. Our method exploits acyclic aryl triazine precursors that undergo a photocyclization reaction upon exposure to violet light (420 nm). Continuous flow reactor technology is exploited to afford excellent yields in only 10 min residence time with no additives or photocatalysts needed. The underlying reaction mechanism appears to be based on an unprecedented variation of the classical Norrish type II reaction with concomitant fragmentation and formation of N-N bonds. Scalability, process robustness, and green credentials of this intriguing transformation are highlighted.

Catalytic Asymmetric Synthesis of α-Mono and α,α-Disubstituted 5- and 6-Membered α-Aza-lactams

AbstractFive- and six-membered cyclic amide structures with an embedded endocyclic α-aza group (α-aza-lactams) not only represent masked or protected forms of α-amino acids, but also form the core of other medicinally relevant compound families such as (thio)hydantoins and di(tri)ketopiperazines. In recent years, catalytic methods have been discovered to synthesize these molecular scaffolds, particularly those bearing an α-stereogenic tri- or tetrasubstituted carbon center, enantioselectively. The wide variety of methods and catalytic activation strategies that have been successfully applied to this end in a short period of years is notable. This short review covers the most significant, highlighting their differences and complementarities. The methods are organized according to the disconnection approach to the target α-aza-lactam structure, which in most cases is deeply bound to the type of catalysis applied.1 Introduction2 Catalyst-Controlled Cα–H Functionalization (Approach a)3 Decarboxylative α-AAA Reactions (Approach b)4 Cα–X Substitution Reactions (Approach c)5 De Novo Synthesis from Acyclic Precursors (Approach d)6 Hydrogenation of (Addition to) α-Alkyliden-α-aza-lactams (Approach e)7 Kinetic Resolution and Deracemization (Approach f)8 Conclusions

Catalyst-free light-mediated polyene cyclization

Polyene cyclization reactions are highly efficient and unique biomimetic transformations that yield complex polycyclic molecules from their acyclic precursors. Various cation-mediated and radical-mediated synthetic methods have been developed to obtain highly diastereoselective cyclizations, along with the use of visible-light in the recent years. In this paper, we report a visible-light-mediated, catalyst-free cascade cyclization of geranyl phenols containing bromo- and chloro-groups at different positions of the phenolic ring. The desired cyclization product was obtained with high stereoselectivity using a blue LED light in hexafluoro-2-propanol without any photocatalyst. The presence of a halogen, and particularly chlorine or bromine is essential for the success of this cyclization, as is the use of blue instead of green LED light. Although the exact reason for this success is unclear, some possible explanations are discussed and further control studies of photoreactions should be a part of any efforts in this area.

Functional characterization of a geranylgeranyl diphosphate synthase in the leaf beetle Monolepta hieroglyphica.

Geranylgeranyl diphosphate synthase (GGPPS) as the short-chain prenyltransferases for catalyzing the formation of the acyclic precursor (E)-GGPP has been extensively investigated in mammals, plants, and microbes, but its functional plasticity is poorly understood in insect species. Here, a single GGPPS in leaf beetle Monolepta hieroglyphica, MhieGGPPS, was functionally investigated. Phylogenetic analysis showed that MhieGGPPS was clustered in one clade with homologs and had six conserved motifs. Molecular docking results indicated that binding sites of dimethylallyl diphosphate (DMAPP), (E)-geranyl pyrophosphate (GPP), and (E)-farnesyl pyrophosphate (FPP) were in the chain-length determination region of MhieGGPPS, respectively. In vitro, recombiant MhieGGPPS could catalyze the formation of (E)-geranylgeraniol against different combinations of substrates including isopentenyl pyrophosphate (IPP)/DMAPP, IPP/(E)-GPP, and IPP/(E)-FPP, suggesting that MhieGGPPS could not only use (E)-FPP but also (E)-GPP and DMAPP as the allylic cosubstrates. In kinetic analysis, the (E)-FPP was most tightly bound to MhieGGPPS than that of others. It was proposed that MhieGGPPS as a multifunctional enzyme is differentiated from the other GGPPSs in the animals and plants, which only accepted (E)-FPP as the allylic cosubstrate. These findings provide valuable insights into understanding the functional plasticity of GGPPS in M. hieroglyphica and the novel biosynthesis mechanism in the isoprenoid pathway.

Recent advances in catalytic enantioselective carbometallation of cyclopropenes and cyclobutenes.

Enantioenriched small carbocycles are key structures in numerous natural products and pharmaceutically important molecules as well as vital intermediates in organic synthesis. Although various catalytic approaches for the construction of such molecules from acyclic precursors have been developed, direct enantioselective functionalization of preformed three-membered and four-membered rings represents the most straightforward and modular strategy, enabling rapid and diversified synthesis of enantioenriched cyclopropanes and cyclobutanes from a single set of starting materials without the need for the incorporation of specific functional groups. In this Feature Article, we have summarized the recent advances in catalytic enantioselective functionalization of cyclopropenes and cyclobutenes through carbometallation. The plausible mechanisms of such reactions and future of this field are also discussed.

Synthetic Routes and Pharmacological Activities of Purine Derivatives: A Review

Abstract: The Purine moiety is regarded as the ubiquitous nitrogen-containing heterocycle in nature and is recognized as a privileged scaffold in medicinal chemistry. Moreover, the purine derivatives are heterocyclic aromatic compounds consisting of conjoined pyrimidine and imidazole moieties. Purine derivatives are involved in various metabolic processes as cofactors associated with a wide variety of enzymes and receptors. Therefore, many synthetic ways to obtain purine derivatives were developed using different reagents such as pyrimidine, imidazole, and some acyclic precursors. This article review focuses on the synthetic methodologies of purine derivatives from its first synthesis in the 19th century to this last decade and also reports a variety of proven pharmacological applications for the purine derivatives. This review offers a panoply of synthetic routes that medicinal and organic chemistry researchers can use in the preparation and design of new purine derivatives.

Synthesis of Tetrahydronaphthoazetidinones, 2,5‐Dioxo‐1,4‐methanobenzoazepines and 3‐Hydroxypyrrolidinones Through Copper‐Assisted Post‐Ugi Reactions

AbstractCopper‐assisted post‐Ugi reactions enable access to different heterocyclic systems, tetrahydronaphthoazetidinone, 2,5‐dioxo‐1,4‐methanobenzoazepine and 3‐hydroxypyrrolidinone derivatives. The described process affords complex scaffolds from readily available acyclic precursors using simple protocols.

Unusually cyclized triterpenoids: occurrence, biosynthesis and chemical synthesis.

Covering: 2009 to 2021Biosynthetically, most of the syntheses of triterpenes follow the cascade cyclization and rearrangement of the acyclic precursors viz., squalene (S) and 2,3-oxidosqualene (OS), which lead to the very well known tetra- and pentacyclic triterpene skeletons. Aside from these, numerous other triterpenoid molecules are also reported from various natural sources and their structures are derived from "S" and "OS" via some unusual cyclization operations which are different from the usual tetra- and pentacyclic frameworks. Numerous compelling advances have been made and reported in the identification of these unusual cyclized mono-, di-, tri- and tetracyclic triterpenes between 2009 and 2021. Besides a dramatic increase in the newly isolated uncommon cyclized triterpenoids, substantial progress in the (bio)-synthesis of these triterpenes has been published along with significant progress in their biological effects. In this review, 180 new unusual cyclized triterpenoids together with their demonstrated biogenetic pathways, syntheses and biological effects will be categorized and discussed.

Farnesyl/geranylgeranyl diphosphate synthases regulate the biosynthesis of alarm pheromone in a unique manner in the vetch aphid Megoura viciae.

Farnesyl/geranylgeranyl diphosphate synthases (FPPS/GGPPS) as the short-chain prenyltransferases catalyse the formation of the acyclic precursors (E)-FPP and (E)-GGPP for isoprenoid biosynthesis. Here, we first cloned the cDNAs encoding FPPS and GGPPS in the vetch aphid Megoura viciae (designated as MvFPPS and MvGGPPS). They had an open reading frame of 1185 and 930 bp in length, encoding 395 and 309 amino acids, with a theoretical isoelectric point of 6.52 and 6.21, respectively. Sequence alignment and phylogenetic analysis showed that MvFPPS and MvGGPPS shared the conserved aspartate-rich motifs characterized by all prenyltransferases identified to date and were clustered with their homologues in two large clades. RNA interference (RNAi) combined with gas chromatography/mass spectrometry (GC-MS) analysis showed that both MvFPPS and MvGGPPS were involved in the biosynthesis of alarm pheromone. Spatiotemporal expression profiling showed that the expression of MvFPPS and MvGGPPS was significantly higher in embryos than in other tissues. RNAi and GC-MS performed specifically in embryos corroborated the function of MvFPPS and MvGGPPS. In vitro, enzymatic activity assay and product analysis demonstrated that MvFPPS could catalysed the formation of (E)-FPP using DMAPP or (E)-GPP as the allylic cosubstrates in the presence of IPP, while MvGGPPS could only use (E)-GPP or (E)-FPP as cosubstrates. Functional interaction analysis using RNAi revealed that MvGGPPS exerts unidirectional functional compensation for MvFPPS. Moreover, it can regulate the biosynthesis of alarm pheromone by imposing a negative feedback regulation on MvFPPS. Our study helps to understand the molecular regulatory mechanism of terpenoid biosynthesis in the aphid.

Halogen-Bonding Heteroditopic [2]Catenanes for Recognition of Alkali Metal/Halide Ion Pairs.

The first examples of halogen bonding (XB) heteroditopic homo[2]catenanes were prepared by discrete Na+ template-directed assembly of oligo(ethylene glycol) units derived from XB donor-containing macrocycles and acyclic bis-azide precursors, followed by a CuI -mediated azide-alkyne cycloaddition macrocyclisation reaction. Extensive 1 H NMR spectroscopic studies show the [2]catenane hosts exhibit positive cooperative ion-pair recognition behaviour, wherein XB-mediated halide recognition is enhanced by alkali metal cation pre-complexation. Notably, subtle changes in the catenanes' oligo(ethylene glycol) chain length dramatically alters their ion-binding affinity, stoichiometry, complexation mode, and conformational dynamics. Solution-phase and single-crystal X-ray diffraction studies provide evidence for competing host-separated and direct-contact ion-pair binding modes. We further demonstrate the [2]catenanes are capable of extracting solid alkali-metal halide salts into organic media.

2,3‐Diodocarbazoles by a Domino Iodocyclization/Iodo‐Translocation of (3‐Iodoindolyl)butynols

AbstractA controlled access to 1‐aryl 2,3‐diiodo‐carbazoles involving iodine transposition has been accomplished directly from acyclic precursors. The 2,3‐diiodo‐carbazole core was prone to further chemoselective decoration at C3−I or double difunctionalization.magnified image

Total Synthesis of Matrine Alkaloids.

The total synthesis of three diastereomeric matrine natural products is reported. The 8-step synthesis commences with simple acyclic precursors, forms all 4 rings of the tetracyclic natural product framework, and forges 10 of the 20 covalent bonds of the target structure. A cross-conjugated triene is positioned at the core of an acyclic branched structure. This precursor collapses to the tetracyclic natural product framework through an orchestrated sequence of two separate intramolecular cycloadditions. A subsequent, late-stage hydrogenation is accompanied by strain-release redox epimerizations to deliver the three natural products. An unprecedented carba-analogue is prepared in the same way. Semisynthetic manipulations of matrine provide access to 10 additional natural products.

Enantioselective Synthesis of α-Alkenylated γ-Lactam Enabled by Ni-Catalyzed 1,4-Arylcarbamoylation of 1,3-Dienes

Enantioselective Synthesis of α-Alkenylated γ-Lactam Enabled by Ni-Catalyzed 1,4-Arylcarbamoylation of 1,3-Dienes

Regioselective Synthesis of 5- and 3-Hydroxy-N-Aryl-1H-Pyrazole-4-Carboxylates and Their Evaluation as Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase.

In silico evaluation of various regioisomeric 5- and 3-hydroxy-substituted alkyl 1-aryl-1H-pyrazole-4-carboxylates and their acyclic precursors yielded promising results with respect to their binding in the active site of dihydroorotate dehydrogenase of Plasmodium falciparum (PfDHODH). Consequently, four ethyl 1-aryl-5-hydroxy-1H-pyrazole-4-carboxylates and their 3-hydroxy regioisomers were prepared by two-step syntheses via enaminone-type reagents or key intermediates. The synthesis of 5-hydroxy-1H-pyrazoles was carried out using the literature protocol comprising acid-catalyzed transamination of diethyl [(dimethylamino)methylene]malonate with arylhydrazines followed by base-catalyzed cyclization of the intermediate hydrazones. For the synthesis of isomeric methyl 1-aryl-3-hydroxy-1H-pyrazole-4-carboxylates, a novel two-step synthesis was developed. It comprises acylation of hydrazines with methyl malonyl chloride followed by cyclization of the hydrazines with tert-butoxy-bis(dimethylamino)methane. Testing the pyrazole derivatives for the inhibition of PfDHODH showed that 1-(naphthalene-2-yl)-5-hydroxy-1H-pyrazole-4-carboxylate and 1-(naphthalene-2-yl)-, 1-(2,4,6-trichlorophenyl)-, and 1-[4-(trifluoromethyl)phenyl]-3-hydroxy-1H-pyrazole-4-carboxylates (~30% inhibition) were slightly more potent than a known inhibitor, diethyl α-{[(1H-indazol-5-yl)amino]methylidene}malonate (19% inhibition).