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Two series of novel hybrid heterocyclic compounds that combine the imidazole ring with bioactive piperidine, morpholine or piperazine heterosystems, through a hydrazone unit, were easily obtained by two competitive pathways. Starting from 5‐amino‐4‐cyanoformimidoyl imidazoles and 1‐aminopiperidine, 4‐aminomorpholine or 1‐amino‐4‐methylpiperazine under mild acidic media led to the selective synthesis of 5‐aminoimidazole 4‐carboxamidrazones, whereas the corresponding 4‐hydrazonoyl cyanide derivatives were obtained under stronger acidic conditions. These highly functionalized imidazoles provide convenient synthetic precursors to a vast array of heterocycles with potential pharmaceutical applications. The reaction mechanisms were elucidated on the basis of experimental assays and in silico calculations. The compounds were screened against colorectal cancer HCT116‐p53 wt cell line, and significant IC50 values of 3.69 μM and 4.83 μM were obtained. [ABSTRACT FROM AUTHOR]

An approach to gem‐difluoro‐3‐azabicyclo[3.n.1]alkane‐ derived building blocks through double‐Mannich addition– deoxofluorination sequence is described. The scope of the method was demonstrated for a series of saturated (hetero)cyclic ketones or ketoesters (including five‐ to seven‐membered cycloalkane derivatives and N‐, O‐, S‐containing saturated heterocycles). Further transformations of functional groups produced various bifunctionalized difluorinated building blocks, namely, N‐protected aminoacids, mono‐N‐Boc‐protected diamines, and unprotected aminoalcohols in good to excellent overall yields. For the azabicyclo[3.3.1]alkane series, a potential for isosteric replacements is demonstrated by evaluation of the key physicochemical properties (i. e., pKa(H) and LogP). [ABSTRACT FROM AUTHOR]

Piperidine 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. [ABSTRACT FROM AUTHOR]

Current medicinal chemistry relies heavily on the quality of building blocks, i. e. reagents used to introduce chemical diversity into the target molecules. The last decade witnessed an emergence of many novel (or well‐overlooked old) chemotypes for drug discovery, which is related to adapting new synthetic methodologies, designing new sp3‐enriched bioisosteres, paying attention to previously underrated (or even unwanted) structural motifs, or combination thereof. In this review with 532 references, a survey of selected chemotypes that emerged recently in medicinal chemistry is provided, with a focus on the synthesis of the corresponding building blocks. Thus, saturated (hetero)aliphatic boronates, sulfonyl fluorides, sulfinates, non‐classical sp3‐enriched benzene isosteres, bicyclic morpholine/piperidine/piperazine analogs, as well as gem‐difluorinated cycloalkanes (as an example of emerging fluorinated motifs) are discussed. [ABSTRACT FROM AUTHOR]

An improved, efficient synthesis of some functionalized saturated azaheterocycles has been accomplished by controlled functionalization of various readily available cyclic compounds containing ring C=C bond. The stereocontrolled synthetic concept was based on the oxidative ring cleavage of various unsaturated scaffolds across ozonolysis followed by ring closing with double reductive amination with primary alkylamines or fluorinated alkylamines. The protocol provided versatile azaheterocyclic derivatives with a piperidine or azepane framework. [ABSTRACT FROM AUTHOR]

The article titled "Front Cover: gem-Difluoro-3-azabicyclo[3.n.1]alkanes and Their Derivatives - Bicyclic Fluorinated Piperidine Isosteres for Drug Discovery" highlights the potential of 9,9-difluoro-3-azabicyclo[3.3.1]alkane as a novel fluorinated three-dimensional piperidine isostere in drug discovery. The compound, synthesized by Ukrainian chemists, is depicted on the front cover as a peaceful night sky above Kyїv city, symbolizing its position in the medicinally relevant chemical space. The article provides more information on this topic and is authored by Serhii Kihakh, Kostiantyn P. Melnykov, Vitalii Bilenko, Serhii Trofymchuk, Oleksandr S. Liashuk, and Oleksandr O. Grygorenko. [Extracted from the article]

The reductive amination (RA) reaction plays a pivotal role in the synthesis of new C–N bonds, due to the availability of many different and low‐cost reagents and their operational simplicity. The introduction in a compound of a nitrogen‐containing moiety that can be reduced to an amine in the reaction medium allows to perform cascade reactions which further expand this method. The application of the intramolecular version of the RA to carbohydrates allows the synthesis of polyhydroxypiperidine iminosugars, which are among the most challenging and fascinating glycomimetics for a synthetic chemist. This minireview focuses on the use of RA and of the double reductive amination (DRA) reaction in the key ring‐closing step en route to the synthesis of these compounds. [ABSTRACT FROM AUTHOR]

An efficient approach towards introducing (cyclo)alkyl substituents at C‐2, C‐3 or C‐4 positions of the piperidine ring was described. The method relied on the straightforward two‐step reaction sequence based on the formal sp3–sp3 retrosynthetic disconnection. The procedure commenced with selective directed ortho metalation of 2‐ and 3‐bromopyridine, followed by reaction with aldehydes or ketones. The optimized methods were developed for all three isomers of hydroxyalkyl‐substituted pyridines, which were synthesized in 28–84 % overall yield (20 examples). Catalytic hydrogenation of these adducts could be performed selectively with or without retention of the hydroxyl group in their molecules, so that either (cyclo)alkylpiperidines (14 examples) or the corresponding saturated amino alcohols (16 examples) were obtained (28–96 % and 82–96 % yield, respectively). After minor modifications, the developed method was also implemented in a flow reactor and a 5 L autoclave, which allowed for the preparation of up to 0.5 kg of the representative (cyclo)alkylpiperidines. [ABSTRACT FROM AUTHOR]

An efficient synthetic approach for the construction of fluorine‐containing piperidine γ‐amino acid derivatives has been developed. The synthetic concept was based on oxidative ring opening of an unsaturated bicyclic γ‐lactam (Vince‐lactam) through its ring C=C bond, followed by double reductive amination of the diformyl intermediate performed with various fluoroalkylamines. The method has been extended towards the access of alkylated and perfluoroalkylated substances and for γ‐lactam derivatives. The transformations proceeded with stereocontrol: the configuration of the stereocenters in the products were predetermined by the configuration of the chiral centers of the starting γ‐lactam. The method could be extended for the access to enantiopure piperidine γ‐amino esters. An stereocontrolled approach for the synthesis of fluorine‐containing piperidine γ‐amino acid derivatives has been developed. The synthetic concept was based on oxidative ring opening of Vince‐lactam, followed by double reductive amination of the diformyl intermediate performed with various fluoroalkylamines. The procedure has been extended towards the access of alkylated and perfluoroalkylated substances and for γ‐lactam derivatives. [ABSTRACT FROM AUTHOR]

Tofacitinib is a Janus activated kinase (JAK) inhibitor approved for the treatment of rheumatoid arthritis and active psoriatic arthritis. Its synthesis normally involves long synthetic sequences due to the chirality associated to the piperidine ring. This review is a comprehensive analysis of the different synthetic methods used to prepare this active pharmaceutical ingredient (API), covering the related journal and patent literature. The synthesis of tofacitinib, a Janus activated kinase (JAK) inhibitor approved for the treatment of rheumatoid arthritis and active psoriatic arthritis, normally involves long sequences due to the chirality of the piperidine ring. This review is a comprehensive analysis of the different methods to prepare this active pharmaceutical ingredient (API), covering the related journal and patent literature. [ABSTRACT FROM AUTHOR]

3,4,5‐Trihydroxypiperidines represent a family of biologically active natural products, found to modulate principally the glycosidase enzymes. This is ascribed to their structural and electronic resemblance to the pyranose monosaccharides, their natural counterparts. Expedient syntheses are crucial to access these valuable high Fsp3 index drug leads. In this review we present the literature strategies to this class of iminosugars to spur further research into drug leads targeting the glycobiological machinery of living systems. 3,4,5‐Trihydroxypiperidines, their derivatives and analogues are biologically active principally as glycosidase modulators. Expedient syntheses are crucial to access these high Fsp3 index drug leads. Syntheses from the chiral pool are reviewed here and their role as drug leads. [ABSTRACT FROM AUTHOR]

Stereoselective and biocatalysed synthetic routes to 3,4,5‐trihydroxypiperidines and their N‐ and O‐derivatisations are reviewed. These iminosugars effectively modulate glycosidase enzymes and display biological activities in immunosuppression, as anti‐inflammatory agents and as anti‐viral agents. Syntheses to these building blocks and their N‐ and O‐derivatives are predicted to produce drug leads of high Fsp3 index. This is also crucial in the collection of structure‐activity relationship data, particularly for diseases dependant on glycosidase modulation. Synthetic routes to 3,4,5‐trihydroxypiperidines via stereoselective and biocatalytic protocols, and strategies to their N‐ and O‐derivatisation are reviewed here. 3,4,5‐Trihydroxypiperidines are high Fsp3 index drug leads belonging to the iminosugar family and displaying biological activitites principally as glycosidase modulators. [ABSTRACT FROM AUTHOR]

Piperidines are currently the most frequently used heterocycles in the development of new pharmaceuticals. A straightforward efficient stereo- and regioselective asymmetric access to chiral polysubstituted piperidines creating multiple stereogenic centers is often still a challenge. Herein we report a rapid approach towards trisubstituted piperidines, which is notable for the use of a readily accessible isoxazolinone starting material and for creating three stereocenters in a single step. 3,4-Dihydropyridines, which are probably formed by a Pd-catalyzed cycle via a decarboxylative oxidative addition of the substrates, appear to be useful intermediates in this relay catalysis, in which Ir acts as enantioselective hydrogenation catalyst to form the valuable chiral heterocycles under mild conditions. [ABSTRACT FROM AUTHOR]

The advantages of performing reactions in continuous flow vs. the classic batch processes render flow chemistry a suitable technique for library synthesis. Inspired by our recent work to create fluorine-containing nitrogen heterocycles and by the potential of the urea group in drug design, we herewith describe the combination of both aspects in the continuous flow synthesis of two libraries of urea derivatives based on the piperidin-4-one scaffold. [ABSTRACT FROM AUTHOR]

Herein we report a convenient, fast, and high-yielding method for the generation of the racemic amide anaesthetics mepivacaine, ropivacaine, and bupivacaine. Coupling of α-picolinic acid and 2,6-xylidine under sealed-vessel microwave conditions generates the intermediate amide after a reaction time of only 5 min at 150 °C. Subsequent reaction in a continuous-flow high-pressure hydrogenator (H-Cube ProTM) in the presence of the respective aldehyde directly converts the intermediate to the final amide anaesthetics in a continuous, integrated, multi-step ring-hydrogenation/reductive amination protocol. Merits and limitations of the protocol are discussed. [ABSTRACT FROM AUTHOR]

The iron-catalyzed synthesis of α-dienyl N-heterocycles is reported. The method is cost-effective, atom-economic, and led to a range of substituted α-dienyl heterocycles in moderate to good yields and diastereoselectivities. The α-dienyl piperidines are key synthetic intermediates as demonstrated by the preparation of a panel of α-polyenyl N-heterocycles. [ABSTRACT FROM AUTHOR]

Vicinal chloroamines derived from glycals have been converted into the corresponding chiral aziridines. Although the formation of a tetrahydrofuran derivative is also possible, reaction conditions were developed to give the azirdines exclusively. One of the aziridines is closely related to a compound used in the synthesis of an advanced intermediate en route to Zanamivir, an antiviral agent. Furthermore, one of the aziridines was converted into a piperidine–azepine fused derivative [ABSTRACT FROM AUTHOR]

The synthesis of 2-(4-methoxyphenyl)-3,4-(dihydroxy)piperidines was accomplished by using ethyl p-methoxycinnamate as the starting material and an acid-mediated amido cyclization reaction as the key step. This short and straightforward strategy avoids extra steps to create the chiral center and does not require a leaving group at the benzylic carbon. This study also showed that the stereochemical outcome of the cyclization reaction is influenced more by allylic 1,3-strain (A1,3 strain) than by the participation of a neighboring group. [ABSTRACT FROM AUTHOR]

Saturated heterocycles, such as THFs, pyrrolidines, piperidines and THPs, are essential components of many biologically active compounds. Examples of C-H functionalization on these important ring systems remain scarce, especially at unactivated positions. Here we report the development of conditions for the palladium-catalyzed stereoselective C(sp3)-H arylation at unactivated 3-positions of 5- and 6-membered N- and O-heterocycles with aminoquinoline directing groups. Subtle differences in substrate structures altered their reactivity significantly; and different conditions were required to achieve high yields in each case. Successful conditions were developed using a short empirical optimization approach to cover reaction space with a limited set of variables. Excellent cis-selectivity was achieved in all cases, except for the THP substrate where minor trans-products were formed through a different palladacyclic intermediate. Here, differences in reactivity and selectivity with other directing groups were examined. [ABSTRACT FROM AUTHOR]

Mannich-type reactions of chiral δ-chloro- N- tert-butanesulfinyl-substituted imidates across N-sulfonyl aldimines resulted in the efficient and anti-stereoselective synthesis of new β-(sulfonylamino)- N-sulfinyl imidates ( dr > 99:1). These compounds were then successfully cyclized to give 2-aryl- N-sulfonylpiperidine-3-( N-sulfinyl)carbimidates in high yields. These proved to be useful intermediates for the synthesis of chiral methyl 2-arylpiperidine-3-carboxylates as well as cis-3-amino-2-aryl- N-sulfonylpiperidines. [ABSTRACT FROM AUTHOR]

The solid-phase conjugation of the antimicrobial peptide c(KKLKKFKKLQ) ( BPC194) to a linear or cyclic sequence through a 1,2,3-triazole ring is described. Cyclic alkynyl-peptidyl resins derived from BPC194 were treated with azidopeptides derived from the antimicrobial peptide BP100 or from the bacteriocin iturin A. The cyclic alkynyl-peptidyl resins incorporated at the 3-position a propargylglycine, a glutamic acid residue derivatized with propargylamine or a lysine bearing a propioloyl group. The reactions of the cyclic alkynyl resins with the BP100-derived azidopeptides depended on the length and the sequence of the azidopeptides. The reactions were performed by treatment of the alkynyl resin with CuI and ascorbic acid, and required the presence of piperidine/DMF or DIEA in 2,6-lutidine/DMF. The latter conditions also allowed the conjugation of the alkynyl-peptidyl resin bearing a propioloyl lysine to a linear or cyclic azidopeptide derived from the cyclic moiety of iturin A. [ABSTRACT FROM AUTHOR]

The Lewis acid promoted reactions of 2-substituted 2-propenyl amides and the 2-methylbuta-2,3-dienyl ester of ethenetricarboxylate have been examined. The reactions of 2-substituted 2-propenyl amides with AlCl3 gave 2-oxo-5,6-dehydropiperidines as the major products. The reaction of 2-methylbuta-2,3-dienyl ester with Lewis acids such as AlCl3 and SnCl4 gave 2-oxo-3,6-dihydropyran as the major product. The preference for six- over five-membered-ring formation was observed. [ABSTRACT FROM AUTHOR]

A simple and highly efficient approach to an enantioenriched 2,6-disubstituted piperidin-3-ol skeleton is developed from an aldehyde as a starting material by using organocatalytic and asymmetric dihydroxylation as the key steps. Its application to the total synthesis of (-)-deoxoprosopinine and (+)-deoxoprosophylline is also reported. [ABSTRACT FROM AUTHOR]

An efficient approach to the multigram preparation of sp SP 3 sp -enriched fluorinated building blocks bearing protected azetidine, pyrrolidine, piperidine, or cyclohexanone moieties and transformations of these useful intermediates into the nitrogen heterocycles mentioned above are described. Keywords: Fluorine; Heterocycles; Pyrazoles; Pyrimidines; Synthetic methods EN Fluorine Heterocycles Pyrazoles Pyrimidines Synthetic methods 1 1 1 04/25/22 20220421 NES 220421 B The Front Cover b shows examples of fluoro-substituted pyrazoles and pyrimidines with saturated heterocyclic substituents - advanced building blocks for organic and medicinal chemistry synthesized by a group of chemists from Kyiv, Ukraine. Front Cover: Fluorine-Containing sp3-Enriched Building Blocks for the Multigram Synthesis of Fluorinated Pyrazoles and Pyrimidines with (Hetero)aliphatic Substituents (Eur. J. Org. [Extracted from the article]

Unbranched, and α- and β-methyl-branched, trihydroxypiperidine α-iminonitriles have been obtained in a single step from protected 5- O-tosylate pentoses. This reaction comprises a one-pot tandem Strecker reaction and iminocyclisation. These trihydroxypiperidine α-iminonitriles are precursors to trihydroxypipecolic acids. No formation of pyrrolidine products was observed. [ABSTRACT FROM AUTHOR]

The application of perfluoroalkylated cyclic imines in azido-Ugi reactions was studied. It was shown that the reaction allows access to five-, six- and seven-membered perfluoroalkylated cyclic amines connected to a tetrazole ring. The scope and limitations of this approach are discussed. When benzyl isocyanide was used in the azido-Ugi reaction, it was shown that the tetrazole products could easily be debenzylated by catalytic hydrogenation to form 1 H-tetrazoles in excellent yields. [ABSTRACT FROM AUTHOR]

The preparation of optically active lactams from 3-aryl-2-piperidinone is reported. The quaternary carbon stereocentres were formed using palladium-catalysed asymmetric allylic alkylation reactions. The resulting enantioenriched compounds are useful intermediates for the synthesis and development of neurokinin antagonists. [ABSTRACT FROM AUTHOR]

An efficient and simple strategy has been developed to synthesize various substituted nitroalkenes involving a cooperative catalytic system of FeCl3 and piperidine. This dual catalytic protocol simultaneously activates both electrophile and nucleophile and works under mild reaction conditions so that many sensitive functional groups were tolerated. Moreover, this cooperative catalytic reaction is also suitable for various one-pot reactions involving nitroalkenes such as, 2 H-chromenes, N-arylpyrrole and Michael reaction with indole. Notably, this method is low-cost, efficient and environmentally friendly. [ABSTRACT FROM AUTHOR]

A practical and efficient two-step protocol for the synthesis of several new 4,6,7,8,8 a,9-hexahydropyrrolo[1,2- a][1,2,3]triazolo[1,5- d]pyrazines is described. The first step involves the AuBr3-catalyzed three-component coupling reaction of terminal alkynes, aldehydes, and amines under solvent-free conditions to provide the requisite propargylamines. The reaction tolerates a high structural diversity, requires only short reaction times, gives high diastereoselectivities, and is environmentally benign. Furthermore, the propargylamine products undergo catalyst-free intramolecular azide-alkyne [3 + 2] dipolar cycloaddition reactions to give the 4,6,7,8,8 a,9-hexahydropyrrolo[1,2- a][1,2,3]triazolo[1,5- d]pyrazines in excellent yields and with excellent diastereoselectivities. [ABSTRACT FROM AUTHOR]

A short and efficient total synthesis of the alkaloid isosolenopsin and its enantiomer has been achieved. The key step was a ω-transaminase-catalysed regioselective monoamination of the diketone pentadecane-2,6-dione, which was obtained in a single step through the application of a Grignard reaction. Initial low conversions in the biotransformation could be overcome by optimisation of the reaction conditions employing suitable cosolvents. In the presence of 20 vol.-% N, N-dimethylformamide (DMF) or n-heptane the best results were obtained by employing two enantiocomplementary ω-transaminases originating from Arthrobacter at 30-40 °C; under these conditions, conversions of more than 99 % and perfect stereocontrol ( ee > 99 %) were achieved. Diastereoselective chemical reduction (H2/Pd/C) of the biocatalytic product gave the target compound. The linear three-step synthesis provided the natural product isosolenopsin in diastereomerically pure form ( ee > 99 %, dr = 99:1) with an overall yield of 64 %. [ABSTRACT FROM AUTHOR]

Cover Feature: An Improved Stereocontrolled Access Route to Piperidine or Azepane -Amino Esters and Azabicyclic - and -Lactams; Synthesis of Novel Functionalized Azaheterocyles (28/2021) Keywords: Amino acids; Azaheterocyles; Functionalization; Ozonolysis; Stereocontrol EN Amino acids Azaheterocyles Functionalization Ozonolysis Stereocontrol 3865 3865 1 08/25/21 20210726 NES 210726 B The Cover Feature b shows the structure of some fluorine-containing azaheterocycles (amino esters, lactams) and the Globe (Terra) which is continuously exposed to pollution and overload with various substances. Amino acids, Azaheterocyles, Functionalization, Ozonolysis, Stereocontrol. [Extracted from the article]

The Front Cover shows the sunset over lake Balaton, Hungary in the background of some novel fluorine‐containing piperidine derivatives. Despite of the fact that fluorinated organic compounds are practically absent in the nature, an increasing number of drugs introduced to the market are containing fluorine. Functionalized fluorine‐containing azaheterocycles have been synthetized with stereocontrol across oxidative ring opening followed by ring closing with double reductive amination. More information can be found in the Full Paper by L. Kiss et al. [ABSTRACT FROM AUTHOR]