Acyclic Precursors Research Articles

Construction of Medium-Sized Rings by Gold Catalysis.

Compounds having cyclic molecular frameworks are highly regarded for their abundance and diverse utilities. In particular, medium-sized carbocycles and heterocycles exist in a broad spectrum of natural products, bioactive therapeutics, and medicinally significant synthetic molecules. Metal-mediated methods have been developed for the preparation of compounds containing a medium-sized ring (MSR) through cyclization of different classes of substrates and acyclic precursors. This review focuses on the methodologies for construction of MSRs via gold catalysis. Given the challenges in enabling the assembly of different ring sizes, we present here accounts on Au-mediated cyclization giving notable 7-membered and medium-sized (8-11-membered ring) structures. Emphasis on the pathway and mode of cyclization and the selection of precursors ranging from structurally biased compounds were outlined. Reactivity patterns and the choice of efficient Au catalysts for controlling reaction performance and selectivity in addition to mechanistic attributes are examined.

Interstellar detection of the highly polar five-membered ring cyanocyclopentadiene

Much like six-membered rings, five-membered rings are ubiquitous in organic chemistry, frequently serving as the building blocks for larger molecules, including many of biochemical importance. From a combination of laboratory rotational spectroscopy and a sensitive spectral line survey in the radio band toward the starless cloud core TMC-1, we report the astronomical detection of 1-cyano-1,3-cyclopentadiene (1-cyano-CPD, c-C5H5CN), a highly polar, cyano derivative of cyclopentadiene. The derived abundance of 1-cyano-CPD is far greater than predicted from astrochemical models that well reproduce the abundance of many carbon chains. This finding implies that either an important production mechanism or a large reservoir of aromatic material may need to be considered. The apparent absence of its closely related isomer, 2-cyano-1,3-cyclopentadiene, may arise from that isomer’s lower stability or may be indicative of a more selective pathway for formation of the 1-cyano isomer, perhaps one starting from acyclic precursors. The absence of N-heterocycles such as pyrrole and pyridine is discussed in light of the astronomical finding of 1-cyano-CPD.

Synthetic Approaches to Non-Tropane, Bridged, Azapolycyclic Ring Systems Containing Seven-Membered Carbocycles

AbstractThis Short Review highlights various synthetic approaches to bridged azabicyclic ring systems containing seven-membered carbocyclic rings. Such ring systems are common to a number of biologically active natural products. The seven-membered ring in such systems is generally formed in one of four ways: 1) cyclization of an acyclic precursor; 2) ring expansion or rearrangement of a different ring size; 3) cycloaddition; and 4) use of a synthetic building block with the seven-membered ring already present. Representative examples of each approach from both total synthesis and methodological studies are discussed, with an emphasis on work publishedin the last twenty years.1 Introduction2 Cyclization Reactions3 Ring Expansions and Rearrangements4 Cycloadditions5 Strategies Involving Seven-Membered Ring Building Blocks6 Conclusion

Synthesis of new symmetric cyclic and acyclic halocurcumin analogues typical precursors for hybridization

It is believed that the synthesis of hybrid molecules containing different biologically relevant moieties would furnish multifunctional drugs with the possible synergism of potential importance for the treatment of cancer, diabetic and Alzheimer diseases. It was envisioned that synthesizing different cyclic and acyclic halocurcumin intermediates would furnish key precursors for hybridization. Thus, starting from vanillin (I) as a naturally occurring compound, several O-haloalkyl derivatives (IIa, IIb and III) have been synthesized and characterized. These derivatives were subjected to Knoevenagel condensation reaction with deferent acyclic and cyclic ketones to afford the corresponding symmetric halocurcumin analogues (IV–VIII). The chemical structures of the newly synthesized curcumin intermediates were confirmed with spectroscopic techniques. These analogues, having primary halogen from both sides, are typical precursors of hybrid curcumin analogues.

Lipophilicity trends upon fluorination of isopropyl, cyclopropyl and 3-oxetanyl groups.

A systematic comparison of lipophilicity modulations upon fluorination of isopropyl, cyclopropyl and 3-oxetanyl substituents, at a single carbon atom, is provided using directly comparable, and easily accessible model compounds. In addition, comparison with relevant linear chain derivatives is provided, as well as lipophilicity changes occurring upon chain extension of acyclic precursors to give cyclopropyl containing compounds. For the compounds investigated, fluorination of the isopropyl substituent led to larger lipophilicity modulation compared to fluorination of the cyclopropyl substituent.

2-Ylidene-1,3-thiazolidines and their nonhydrogenated analogs: methods of synthesis and chemical properties

The review summarizes and systematizes the literature data on the methods of synthesis and chemical properties of 2-ylidene-1,3-thiazolidines and 2-ylidene-2,3-dihydro-1,3-thiazoles. Two general approaches to their preparation have been identified: the construction of the 2-ylidene-1,3-thiazolidine ring from acyclic precursors in one synthetic process and the introduction of the 2-ylidene fragment into the 1,3-thiazolidine ring. The main chemical transformations of 2-ylidene-1,3-thiazolidines and 2-ylidene-2,3-dihydro-1,3-thiazoles, which include the reactions of selective functionalization and heterocyclization at the ylidene fragment and thiazolidine backbone, are considered. The bibliography of the review consists of 97 references published from 2000 to 2020.

Improved and Flexible Synthetic Access to the Spiroindole Backbone of Cebranopadol.

By changing the dimethylamino to a nitro group, a novel synthetic access to the spirocyclic opioid analgesic cebranopadol was developed that is much more efficient compared with the established route. On the basis of the α-acidity of α-nitrotoluene, the two-fold Michael addition to acrylate gave an acyclic precursor compound, which was easily transformed by Dieckmann condensation and decarboxylation to the cyclohexanone derivative needed for the annulation of the indole ring by an oxa-Pictet-Spengler reaction. As an additional benefit, the reduction of the nitro group furnished an amine, which could be late-stage-diversified to carboxamides, sulfonamides, ureas, and N-alkyl congeners. The transformation of the nitro group at the spirocyclic scaffold to the dimethylamino function of the actual title compound was achieved in one step with zinc/formic acid/formaldehyde in 83% yield.

Recent Advances in Organocatalyst‐Mediated Benzannulation Reactions

AbstractAromatic compounds are omnipresent in organic chemistry, which are the broadest skeletons of bioactive molecules, medicines, and materials. Due to their importance, conventional methods to assemble aromatic rings have attracted considerable attention. The direct formation of benzene cores from readily available acyclic precursors offers a highly versatile and superior approach to prepare both small organic molecules and sophisticated natural products. Recently, organocatalyst‐mediated annulation reaction, including phosphine‐, tertiary amine‐, secondary amine‐, primary amine‐, and NHC‐mediated benzannulation reactions, is considered as an efficient method to access multi‐substituted arenes. In this review, we will emphasize the selected examples of organocatalyst‐mediated benzannulation reactions of available acyclic precursors for the construction of diverse aromatics.magnified image

Synthesis and Isomerization of the 2-Methyl Enal Fragment of Acyclic Precursors to 9,11-Diene Analogs of Epothilones

Yamaguchi esterification of (2Z,5S,6E)-5-(hydroxymethyl)-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)hepta-2,6-dienal with (2R,5R,6S,7S)-2-(methoxymethoxy)-3,3,5,7-tetramethyl-4-oxo-9-[(1-phenyl-1H-tetrazol-5-yl)sulfonyl-6-[(triethylsilyl)oxy]nonanoic acid afforded the expected acyclic ester. Acid- and base-catalyzed Z,E-isomerization in the 2-methyl enal fragment of acyclic precursors was revealed.

Intramolecular Nicholas Reactions in the Synthesis of Heteroenediynes Fused to Indole, Triazole, and Isocoumarin.

The applicability of an intramolecular Nicholas reaction for the preparation of 10-membered O- and N-enediynes fused to indole, 1,2,3-triazole, and isocoumarin was investigated. The general approach to acyclic enediyne precursors fused to heterocycles includes inter- and intramolecular buta-1,3-diyne cyclizations with the formation of iodoethynylheterocycles, followed by Sonogashira coupling. The nature of both a heterocycle and a nucleophilic group affects the possibility of a 10-membered ring closure by the Nicholas reaction. Among oxacycles, an isocoumarin-fused enediyne was obtained. In the case of O-enediyne annulated with indole, instead of the formation of a 10-membered cycle, BF3-promoted addition of an OH-group to the proximal triple bond at the C3 position afforded dihydrofuryl-substituted indole. For 1,2,3-triazole-fused analogues, using NH-Ts as a nucleophilic functional group allowed obtaining 10-membered azaenediyne, while the substrate with a hydroxyl group gave only traces of the desired 10-membered oxacycle. An improved method for the deprotection of Co-complexes of cyclic enediynes using tetrabutylammonium fluoride in an acetone/water mixture and the investigation of the 10-membered enediynes' reactivity in the Bergman cyclization are also reported. In the solid state, all synthesized iodoethynylheterocycles were found to be involved in halogen bond (XB) formation with either O or N atoms as XB acceptors.

Synthesis of an Oxathiolane Drug Substance Intermediate Guided by Constraint-Driven Innovation.

A new route was developed for construction of the oxathiolane intermediate used in the synthesis of lamivudine (3TC) and emtricitabine (FTC). We developed the presented route by constraining ourselves to low-cost, widely available starting materials—we refer to this as supply-centered synthesis. Sulfenyl chloride chemistry was used to construct the framework for the oxathiolane from acyclic precursors. This bond construction choice enabled the use of chloroacetic acid, vinyl acetate, sodium thiosulfate, and water to produce the oxathiolane.

The Dötz Benzannulation Reaction: A Booming Methodology for Natural Product Synthesis

AbstractSince its finding in 1975, the Dötz benzannulation reaction has attracted a great attention of the scientific community as it permits the regio‐controlled construction of functionalised aromatic frameworks from acyclic precursors. In recent years, this beautifully simple yet much powerful technique for the formation of C−C bonds has opened‐up new possibilities in modern synthetic organic chemistry. In this Review, we report the developments in natural products synthesis by employing the Dötz benzannulation as a key transformation. Although, a flow of publications have witnessed a constant progress in this wonderful area of research, but to our best knowledge this is the first review which purely focuses on the applications of the Dötz benzannulation reaction in natural product synthesis. We are assured that this review will act as a promoter in amplifying the applications of the Dötz benzannulation in the domain of synthetic organic chemistry.

Microwave-Assisted Synthesis of 2-Substituted 2-Thiazolines and 5,6-Dihydro-4H-1,3-thiazines

An efficient and general method for the synthesis of 2-substituted thiazolines and 5,6-dihydro-4H-1,3-thiazines is developed via microwave-assisted ring closure of ω-thioamidoalcohols promoted by ethyl polyphosphate (PPE). The cyclization reaction involves an SN2-type mechanism and features the advantages of very short reaction times, high yields and a predictable stereochemical outcome. The acyclic precursors are prepared in high overall yields by an improved diacylation–thionation–saponification sequence from commercially available ω-amino­alcohols. The whole process is metal-free and operationally simple.

Microwave-assisted synthesis of 2-substituted 4,5,6,7-tetrahydro-1,3-thiazepines from 4-aminobutanol.

A general procedure for the synthesis of 2-substituted tetrahydro-1,3-thiazepines by MW-assisted cyclization of 4-thioamidobutanols is presented. The acyclic precursors were prepared in high overall yields by an expeditious three-step diacylation/thionation/deprotection sequence from 4-aminobutanol. Microwave-assisted ring closure of 4-thioamido alcohols promoted by trimethylsilyl polyphosphate (PPSE) in solvent-free conditions allowed for the synthesis of several hitherto unreported seven-membered iminothioethers bearing 2-aryl, alkenyl, aralkyl and alkyl substituents. The cyclodehydration reaction is likely to involve an SN2-type displacement and affords good to excellent yields of the desired heterocycles in very short reaction times.

Synthesis of 3‐aryl pyrrolidines: A highlights

AbstractPyrrolidine derivatives are very important families of heterocyclic compounds that show diverse biological activity. The substitution pattern and functionalization on these derivatives show different biological activities. Different substituted pyrrolidines shown to have different antibacterial effects. They are also used as scaffolds in the synthesis of unnatural oligomers which have various biological applications in the field of antidiabetic, anticancer, antimalarial, antiviral, antimicrobial, anti‐inflammatory, and antibacterial activities. Numerous groups have synthesized substituted pyrrolidines and they constructed the pyrrolidine ring by the formation of various different bonds from acyclic precursors. Some of the groups have synthesized that derivatives only by reduction.

Synthesis, characterization and Cytotoxicity Evaluation of New Heterocyclic Compounds with Oxazole Ring Containing 4-(Phenylsulfonyl)phenyl Moiety

The paper presents the synthesis, characterization and cytotoxicity assessment of five organic compounds containing 4-(phenylsulfonyl)phenyl fragment in the molecule, namely of three acyclic precursors derived from phenylalanine (from N-acyl-a-amino acids, N-acyl-a-amino acyl chlorides and N-acyl-a-amino ketones class) and of the cyclization products: a 1,3-oxazol-5(4H)-one and, respectively, a 1,3-oxazole substituted in position 5 with the p-tolyl group. The synthesized compounds were characterized by spectral methods (UV-Vis, FT-IR, 1H-NMR, 13C-NMR, and MS) and elemental analysis, which confirmed their structures. For the determination of the purity of the new compounds, the RP-HPLC method was used. In view of the therapeutic potential of the newly synthesized compounds, we evaluated their toxicological profile using the Daphnia magna bioassay.

Synthesis, characterization and Cytotoxicity Evaluation of New Heterocyclic Compounds with Oxazole Ring Containing 4-(Phenylsulfonyl)phenyl Moiety

The paper presents the synthesis, characterization and cytotoxicity assessment of five organic compounds containing 4-(phenylsulfonyl)phenyl fragment in the molecule, namely of three acyclic precursors derived from phenylalanine (from N-acyl-a-amino acids, N-acyl-a-amino acyl chlorides and N-acyl-a-amino ketones class) and of the cyclization products: a 1,3-oxazol-5(4H)-one and, respectively, a 1,3-oxazole substituted in position 5 with the p-tolyl group. The synthesized compounds were characterized by spectral methods (UV-Vis, FT-IR, 1H-NMR, 13C-NMR, and MS) and elemental analysis, which confirmed their structures. For the determination of the purity of the new compounds, the RP-HPLC method was used. In view of the therapeutic potential of the newly synthesized compounds, we evaluated their toxicological profile using the Daphnia magna bioassay.

Synthesis, characterization and Cytotoxicity Evaluation of New Heterocyclic Compounds with Oxazole Ring Containing 4-(Phenylsulfonyl)phenyl Moiety

The paper presents the synthesis, characterization and cytotoxicity assessment of five organic compounds containing 4-(phenylsulfonyl)phenyl fragment in the molecule, namely of three acyclic precursors derived from phenylalanine (from N-acyl-a-amino acids, N-acyl-a-amino acyl chlorides and N-acyl-a-amino ketones class) and of the cyclization products: a 1,3-oxazol-5(4H)-one and, respectively, a 1,3-oxazole substituted in position 5 with the p-tolyl group. The synthesized compounds were characterized by spectral methods (UV-Vis, FT-IR, 1H-NMR, 13C-NMR, and MS) and elemental analysis, which confirmed their structures. For the determination of the purity of the new compounds, the RP-HPLC method was used. In view of the therapeutic potential of the newly synthesized compounds, we evaluated their toxicological profile using the Daphnia magna bioassay. Keywords: N-acyl-a-amino acid, 1,3-oxazol-5(4H)-one, N-acyl-a-amino ketone, 1,3-oxazole, cytotoxic effect

Calyciphylline B-type Alkaloids: Evolution of a Synthetic Strategy to (-)-Daphlongamine H.

We provide a full account of our synthetic studies targeting the hexacyclic calyciphylline B-type alkaloids, a subfamily of the Daphniphyllum natural products. Following an initial set of synthetic strategies focused on constructing the piperidine core of the calyciphylline B-type framework via a 6π-azaelectrocyclization, as well as exploiting the reactivity of underexplored oxazaborinine heterocycles, we ultimately designed a highly functionalized acyclic precursor which underwent carefully orchestrated and efficient cyclizations to forge the architecturally complex natural product scaffold. Our efforts have culminated in the development of the first total synthesis of (-)-daphlongamine H, provided access to its C5-epimer, (-)-isodaphlongamine H, and led to structural revision of deoxyisocalyciphylline B.

SYNTHESIS OF 3-ARYLIDENEPYRROLIDINES

The review summarizes methods of synthesis of 3-arylidenepyrrolidines, illustrated by the most typical examples, published in 2017–2019. The methods are divided into three main groups: modification of the 1-pyrroline (pyrrolidine) ring, intramolecular and intermolecular cyclization of unsaturated acyclic precursors.