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Rigid bicycles are becoming more popular in the pharmaceutical industry because they allow for expansion to new and unique chemical spaces. This work describes a new strategy to construct 2‐azanorbornanes, which can act as rigid piperidine/pyrrolidine scaffolds with well‐defined exit vectors. To achieve the synthesis of 2‐azanorbornanes, new strain‐release reagent, azahousane, is introduced along with its photosensitized strain‐release formal cycloaddition with alkenes. Furthermore, new reactivity between a housane and an imine is disclosed. Both strategies lead to various substituted 2‐azanorbornanes with good selectivities. [ABSTRACT FROM AUTHOR]

1‐Azaspiro[3.3]heptanes were synthesized, characterized, and validated biologically as bioisosteres of piperidine. The key synthesis step was thermal [2+2] cycloaddition between endocyclic alkenes and the Graf isocyanate, ClO2S−NCO, to give spirocyclic β‐lactams. Reduction of the β‐lactam ring with alane produced 1‐azaspiro[3.3]heptanes. Incorporation of this core into the anesthetic drug bupivacaine instead of the piperidine fragment resulted in a new patent‐free analogue with high activity. [ABSTRACT FROM AUTHOR]

Nitrogen heterocycles play a vital role in pharmaceuticals and natural products, with the six‐membered aromatic and aliphatic architectures being commonly used. While synthetic methods for aromatic N‐heterocycles are well‐established, the synthesis of their aliphatic functionalized analogues, particularly piperidine derivatives, poses a significant challenge. In that regard, we propose a stepwise dearomative functionalization reaction for the construction of highly decorated piperidine derivatives with diverse functional handles. We also discuss challenges related to site‐selectivity, regio‐ and diastereoselectivity, and provide insights into the reaction mechanism through mechanistic studies and density functional theory computations. [ABSTRACT FROM AUTHOR]

A copper‐catalyzed dearomative alkynylation of pyridines is reported with excellent regio‐ and enantioselectivities. The synthetically valuable enantioenriched 2‐alkynyl‐1,2‐dihydropyridine products afforded are generated from the readily available feedstock, pyridine, and commercially available terminal alkynes. The three‐component reaction between a pyridine, a terminal alkyne, and methyl chloroformate employs copper chloride and StackPhos, a chiral biaryl P,N‐ ligand, as the catalytic system. Under mild reaction conditions, the desired 1,2‐addition products are delivered in up to 99 % yield with regioselectivity ratios up to 25 : 1 and enantioselectivities values of up to 99 % ee. Activated and non‐activated terminal alkynes containing a wide range of functional groups are well tolerated. Even acetylene gas delivered mono‐alkynylated products in high yield and ee. Application of the methodology in an efficient enantioselective synthesis of the chiral piperidine indolizidine, coniceine, is reported. [ABSTRACT FROM AUTHOR]

With the well‐documented chemical and biological applications, piperidine and pyridine are among the most important N‐heterocycles, and a new synthetic strategy, especially one with an alternative bond‐forming design, is of general interest. Using the gold‐catalyzed intermolecular condensation of amine and diyne‐ene, we report herein the first example of enantioselective 1,2‐dihydropyridine synthesis through a formal [3+2+1] fashion (up to 95 % yield, up to 99 % e.e.). [ABSTRACT FROM AUTHOR]

We report a synthetic endeavor towards the highly strained pentacyclic caged framework of the mavacuran alkaloids which culminated with the concise total synthesis of C‐fluorocurine, C‐profluorocurine, C‐mavacurine, normavacurine, 16‐epi‐pleiocarpamine and taberdivarine H. We designed a strategy involving late‐stage construction of the D ring by Michael addition of a vinylic nucleophile to a 2‐indolyl acrylate moiety. While the intramolecular Michael addition did not succeed, we were able to perform a diastereoselective unusual intermolecular 1,4‐addition of a functionalized vinyl lithium reagent to a readily accessible Michael acceptor with the assistance of the piperidine nitrogen atom through the formation of a complex as suggested by DFT computations. Final cyclization was achieved by nucleophilic substitution to form an ammonium intermediate. The first total syntheses of C‐profluorocurine and C‐fluorocurine were finalized by the dihydroxylation of C‐mavacurine and a pinacol rearrangement, respectively. [ABSTRACT FROM AUTHOR]

We disclose herein a catalytic borrowing hydrogen method that enables an unprecedented, economical one‐pot access to enantiopure tetrahydropyridines with minimal reagent use or waste formation. This method couples a few classes of readily available substrates with commercially available 1,3‐amino alcohols, and delivers the valuable tetrahydropyridines of different substitution patterns free of N‐protection. Such transformations are highly challenging to achieve, as multiple redox steps need to be realized in a cascade and numerous side reactions including a facile aromatization have to be overcome. Highly diastereoselective functionalizations of tetrahydropyridines also result in a general access to enantiopure di‐ and tri‐substituted piperidines, which ranks the topmost frequent N‐heterocycle in commercial drugs. [ABSTRACT FROM AUTHOR]

Starke und sterisch umzäunte Imidodiphosphorimidatkatalysatoren (IDPi) ermöglichen hochenantioselektive Substitutionen von zyklischen, aliphatischen Hemiaminalethern mit Enolsilanen. 2‐Substituierte Pyrrolidine, Piperidine und Azepane werden mit hoher Enantioselektivität erhalten, und die Methode zeigt eine breite Toleranz gegenüber verschiedenen Enolsilanen. Mehrere Naturstoffe lassen sich mit dieser Methode gewinnen. Mechanistische Studien bestärken die Bildung des Ionenpaares zwischen nicht‐stabilisierten, zyklischen N‐(exo‐Acyl)iminiumionen, und dem sterisch umzäunten chiralen Gegenanion. Theoretische Studien legen Übergangszustände nahe, welche die beobachtete Enantioselektivität erklären. [ABSTRACT FROM AUTHOR]

Piperidine and δ‐Lactam chemicals have wide application, which are currently produced from fossil resource in industry. Production of this kind of chemicals from lignocellulosic biomass is of great importance, but is challenging and the reported routes give low yield. Herein, we demonstrate the strategy to synthesize 2‐methyl piperidine (MP) and 6‐methylpiperidin‐2‐one (MPO) from biomass‐derived triacetic acid lactone (TAL) that is produced microbially from glucose. In this route, TAL was firstly converted into 4‐hydroxy‐6‐methylpyridin‐2(1H)‐one (HMPO) through facile aminolysis, subsequently HMPO was selectively transformed into MP or MPO over Ru catalysts supported on beta zeolite (Ru/BEA‐X, X is the molar ratio of Si to Al) via the tandem reaction. It was found that the yield of MP could reach 76.5 % over Ru/BEA‐60 in t‐BuOH, and the yield of MPO could be 78.5 % in dioxane. Systematic studies reveal that the excellent catalytic performance of Ru/BEA‐60 was closely correlated with the cooperative effects between active metal and acidic zeolite with large pore geometries. The related reaction pathway was studied on the basis of control experiments. [ABSTRACT FROM AUTHOR]

We report herein the enantioselective total synthesis of three monoterpene indole alkaloids, namely, (+)‐alstilobanine C, (+)‐undulifoline, and (−)‐alpneumine H. The key features of our synthesis include: a) introduction of chirality via enantioselective deprotonation of a prochiral 4‐substituted cyclohexanone; b) use of methoxymethyl (MOM) ether as both a hydroxyl protective group and a latent oxonium species for the formation of bridged oxepane and c) domino double reductive cyclization to build both the indole and the piperidine ring at the end of the synthesis. The synthesis confirmed the absolute configuration of these natural products assigned based on the biogenetic hypothesis. [ABSTRACT FROM AUTHOR]

The complexes formed between carbon allotropes (C20, C60 fullerenes, graphene, and single‐wall carbon nanotubes) and piperidine have been investigated by means of computational quantum chemical and experimental IR and NMR techniques. Alongside hydrogen bonds, the C⋅⋅⋅N tetrel bond, and lone‐pair⋅⋅⋅π interactions, the unexpected N→C dative/covalent bond has been detected solely in complexes of fullerenes with piperidine. Non‐planarity and five‐member rings of carbon allotropes represent the key structural prerequisites for the unique formation of a dative N→C bond. The results of thermodynamics calculations, molecular dynamics simulations, and NMR and FTIR spectroscopy explain the specific interactions between C60 and piperidine. The differences in behavior of individual carbon allotropes in terms of dative bonding formation brings a new insight into their controllable organic functionalization. [ABSTRACT FROM AUTHOR]

Pyrrolidine and piperidine derivatives bearing halide functional groups are prevalent building blocks in drug discovery as halides can serve as an anchor for post‐modifications. In principle, one of the simplest ways to build these frameworks is the haloamination of alkenes. While progress has been made in this field, notably with the development of enantioselective versions, this reaction is still fraught with limitations in terms of reactivity. Besides, a major question remaining is to understand the mechanism at work. The formation of a haliranium intermediate is typically mentioned, but limited mechanistic evidence supports it. Reported here is an efficient metal‐ and oxidant‐free protocol to achieve the haloamidation of olefins, promoted by hexafluoroisopropanol, along with a DFT investigation of the mechanism. These findings should guide the future development of more complex transformations in the field of halofunctionalization. [ABSTRACT FROM AUTHOR]

We report a RhIII‐catalyzed regio‐ and diastereoselective synthesis of δ‐lactams from readily available acrylamide derivatives and unactivated alkenes. The reaction provides a rapid route to a diverse set of δ‐lactams in good yield and stereoselectivity, which serve as useful building blocks for substituted piperidines. The regioselectivity of the reaction with unactivated terminal alkene is significantly improved by using Cpt ligand on the RhIII catalyst. The synthetic utility of the reaction is demonstrated by the preparation of a potential drug candidate containing a trisubstituted piperidine moiety. Mechanistic studies show that the reversibility of the C−H activation depends on the choice of Cp ligand on the RhIII catalyst. The irreversible C−H activation is observed and becomes turnover‐limiting with [CptRhCl2]2 as catalyst. [ABSTRACT FROM AUTHOR]

The first asymmetric PdII‐catalyzed aminofluorination of unactivated alkenes using chiral quinoline‐oxazolines (Quox) as ligands has been developed. This reaction provides easy access to a wide array of enantiomerically enriched β‐fluoropiperidines in good yields and with excellent enantioselectivity. Notably, Et4NF⋅3 HF as a readily accessible nucleophilic fluoride source was found to play an essential role in the enantioselective control, and CsOCF3 also acts a key additive to improve the excellent ee value of products. [ABSTRACT FROM AUTHOR]

One of the major challenges in organic synthesis is the activation or deconstructive functionalization of unreactive C(sp3)–C(sp3) bonds, which requires using transition or precious metal catalysts. We present here an alternative: the deconstructive lactamization of piperidines without using transition metal catalysts. To this end, we use 3‐alkoxyamino‐2‐piperidones, which were prepared from piperidines through a dual C(sp3)–H oxidation, as transitory intermediates. Experimental and theoretical studies confirm that this unprecedented lactamization occurs in a tandem manner involving an oxidative deamination of 3‐alkoxyamino‐2‐piperidones to 3‐keto‐2‐piperidones, followed by a regioselective Baeyer–Villiger oxidation to give N‐carboxyanhydride intermediates, which finally undergo a spontaneous and concerted decarboxylative intramolecular translactamization. [ABSTRACT FROM AUTHOR]

Asymmetric PdII‐catalyzed intramolecular aminotrifluoromethoxylation of unactivated alkenes using readily accessible and stable CsOCF3 as a trifluoromethoxide source has been developed, which affords a wide variety of enantiomerically enriched β‐substituted OCF3‐containing piperidines in good yields. Introducing a sterically bulky group into pyridine‐oxazoline (Pyox) ligands is crucial to increasing both reactivity and enantioselectivity for the reaction. Additionally, the reaction features good functional group compatibility and mild reaction conditions. [ABSTRACT FROM AUTHOR]

Even though there are dozens of biologically active 2‐substituted and 2,6‐disubstituted piperidines, only a limited number of approaches exist for their synthesis. Herein is described two Mannich‐type additions to nitrones, one using β‐ketoacids under catalyst‐free conditions and another using methyl ketones in the presence of chiral thioureas, which can generate a broad array of such 2‐substituted materials, as well as other ring variants, in the form of β‐N‐hydroxy‐aminoketones. Both processes have broad scope, with the latter providing products with high enantioselectivity (up to 98 %). The combination of these methods, along with other critical steps, has enabled 8‐step total syntheses of the 2,6‐disubstituted piperidine alkaloids (−)‐lobeline and (−)‐sedinone. [ABSTRACT FROM AUTHOR]

Axially chiral 4‐arylisoquinolones are endowed with pronounced bioactivity, and methods for their efficient synthesis have gained widespread attention. However, enantioselective synthesis of axially chiral 4‐arylisoquinolones by means of C−H activation has not been reported to date. Described here is a rhodium (III)‐catalyzed C−H bond activation and annulation for the atroposelective synthesis of axially chiral 4‐arylisoquinolones. The method employs chiral cyclopentadienyl ligands embodying a piperidine ring as backbone and yields the atropisomers with good to excellent yields and enantioselectivity. Biological relevance of the 4‐arylisoquinolones was demonstrated by their investigation in different cellular assays, leading to the discovery of novel non‐SMO (SMO= smoothened) binding Hedgehog pathway inhibitors. [ABSTRACT FROM AUTHOR]

Abstract: Multinuclear solid‐state NMR studies of Cp*2Sc−R (Cp*=pentamethylcyclopentadienyl; R=Me, Ph, Et) and DFT calculations show that the Sc−Et complex contains a β‐CH agostic interaction. The static central transition 45Sc NMR spectra show that the quadrupolar coupling constants (Cq) follow the trend of Ph≈Me>Et, indicating that the Sc−R bond is different in Cp*2Sc−Et compared to the methyl and phenyl complexes. Analysis of the chemical shift tensor (CST) shows that the deshielding experienced by Cβ in Sc−CH2CH3 is related to coupling between the filled σC‐C orbital and the vacant π S c ⋯ H C * orbital. [ABSTRACT FROM AUTHOR]

Abstract: Ligand‐enabled aza‐Heck cyclizations and cascades of N‐(pentafluorobenzoyloxy)carbamates are described. These studies encompass the first examples of efficient non‐biased 6‐exo aza‐Heck cyclizations. The methodology provides direct and flexible access to carbamate protected pyrrolidines and piperidines. [ABSTRACT FROM AUTHOR]

The reaction of rhodium-bound carbenes with strained bicyclic methylene aziridines results in a formal [3+1] ring expansion to yield highly substituted methylene azetidines with excellent regio- and stereoselectivity. The reaction appears to proceed through an ylide-type mechanism, where the unique strain and structure of the methylene aziridine promotes a ring-opening/ring-closing cascade that efficiently transfers chirality from substrate to product. The resultant products can be elaborated into new azetidine scaffolds containing vicinal tertiary-quaternary and even quaternary-quaternary stereocenters. [ABSTRACT FROM AUTHOR]

An iridium-catalyzed cyclocondensation of amino alcohols and aldehydes is reported. Intramolecular allylic substitution by an enamine intermediate and subsequent in situ reduction furnishes 3,4-disubstituted piperidines with high enantiospecificity and good diastereoselectivity. The modular approach and the broad functional group tolerance provide access to diverse piperidine derivatives, which were further functionalized to give a versatile set of products. [ABSTRACT FROM AUTHOR]

The 2-substituted piperidine core is found in drugs (18 FDA-approved drugs), however, their spirocyclic analogues remain unknown. Described here is the synthesis of spirocyclic analogues for 2-substituted piperidines and a demonstration of their validation in drug discovery. [ABSTRACT FROM AUTHOR]

ATAD2 is a cancer-associated protein whose bromodomain has been described as among the least druggable of that target class. Starting from a potent lead, permeability and selectivity were improved through a dual approach: 1) using CF2 as a sulfone bio-isostere to exploit the unique properties of fluorine, and 2) using 1,3-interactions to control the conformation of a piperidine ring. This resulted in the first reported low-nanomolar, selective and cell permeable chemical probe for ATAD2. [ABSTRACT FROM AUTHOR]

An efficient, modular and straightforward entry to tetrahydropyridines and piperidines is reported. This reaction is based on a formal intramolecular hydroalkylation of readily available, properly substituted ynamides which, upon simple activation under acidic conditions, generate highly reactive activated keteniminium ions whose reactivity can be finely controlled to induce a remarkably efficient [1,5]-hydride shift from unactivated C−H bonds and trigger a cationic cyclization which is complete within minutes. [ABSTRACT FROM AUTHOR]

When activated by an acylating agent, pyridine boronic esters react with organometallic reagents to form a dihydropyridine boronic ester. This intermediate allows access to a number of valuable substituted pyridine, dihydropyridine, and piperidine products. [ABSTRACT FROM AUTHOR]

Chirale α-Aminoketone sind hervorragende Nukleophile für hoch stereoselektive Palladium-katalysierte allylische Alkylierungen, sowohl mit chiralen als auch achiralen Allylsubstraten, wobei die Steuerung über das chirale Ketonenolat überwiegt. Die erhaltenen substituierten Aminoketone lassen sich anschließend stereoselektiv reduzieren, wobei bis zu fünf benachbarte Stereozentren erhalten werden können. Dies ermöglicht auch den Aufbau eines hoch substituierten Piperidinderivates. [ABSTRACT FROM AUTHOR]

A newly developed P,N-bidentate ligand enables enantioselective intramolecular cyclopropanation by a reactive α-oxo gold carbene intermediate generated in situ. The ligand design is based on our previously proposed structure (with a well-organized triscoordinated gold center) of the carbene intermediate in the presence of a P,N-bidentate ligand. A C2-symmetric piperidine ring was incorporated in the ligand as the nitrogen-containing moiety. A range of racemic transformations of α-oxo gold carbene intermediates have been developed recently, and this new class of chiral ligands could enable their modification for asymmetric synthesis, as demonstrated in this study. [ABSTRACT FROM AUTHOR]

Enantioselective catalytic intermolecular 1,3-dipolar cycloadditions are powerful methods for the synthesis of heterocycles. In contrast, intramolecular enantioselective 1,3-dipolar cycloadditions are virtually unexplored. A highly enantioselective synthesis of natural-product-inspired pyrrolidino-piperidines by means of an intramolecular 1,3-dipolar cycloaddition with azomethine ylides is now reported. The method has a wide scope and yields the desired cycloadducts with four tertiary stereogenic centers with up to 99 % ee. Combining the enantioselective catalytic intramolecular 1,3-dipolar cycloaddition with a subsequent diastereoselective intermolecular 1,3-dipolar cycloaddition yielded complex piperidino-pyrrolizidines with very high stereoselectivity in a one-pot tandem reaction. [ABSTRACT FROM AUTHOR]

Highly diastereoselective metalloamination/cyclization reactions of zinc(II) hydrazides obtained through reaction of diethylzinc with N, N-dimethylhydrazinoalkenes are described. The resulting organozinc intermediates undergo facile allylation and acylation, in situ, to provide the corresponding functionalized piperidines and pyrrolidines. [ABSTRACT FROM AUTHOR]

The first example of C alkylation of 1,2-dihydropyridines with alkyl triflates and Michael acceptors was developed to introduce quaternary carbon centers with high regio- and diastereoselectivity. Hydride or carbon nucleophile addition to the resultant iminium ion also proceeded with high diastereoselectivity. Carbon nucleophile addition results in an unprecedented level of substitution to provide piperidine rings with adjacent tetrasubstituted carbon atoms. [ABSTRACT FROM AUTHOR]

Minimalist secondary structure mimics are typically made to resemble one interface in a protein-protein interaction (PPI), and thus perturb it. We recently proposed suitable chemotypes can be matched with interface regions directly, without regard for secondary structures. Here we describe a modular synthesis of a new chemotype 1, simulation of its solution-state conformational ensemble, and correlation of that with ideal secondary structures and real interface regions in PPIs. Scaffold 1 presents amino acid side-chains that are quite separated from each other, in orientations that closely resemble ideal sheet or helical structures, similar non-ideal structures at PPI interfaces, and regions of other PPI interfaces where the mimic conformation does not resemble any secondary structure. 68 different PPIs where conformations of 1 matched well were identified. A new method is also presented to determine the relevance of a minimalist mimic crystal structure to its solution conformations. Thus dld- 1 faf crystallized in a conformation that is estimated to be 0.91 kcal mol−1 above the minimum energy solution state. [ABSTRACT FROM AUTHOR]

Aspidophylline A belongs to the akuammiline alkaloid family, the members of which possess intriguing cagelike structures and diverse biological activities. Herein we report a 15-step synthesis of this alkaloid from conveniently available starting materials. The key elements of the synthesis include an intramolecular oxidative coupling to create the tetracyclic furoindoline motif of the natural product and a [Ni(cod)2]-mediated cyclization to install its piperidine ring. [ABSTRACT FROM AUTHOR]

Die Reaktion eines α ‐ Ketoaldehyds und eines terminalen Alkins in Gegenwart von Piperidin und einer katalytischen Menge von AuCl liefert 1,2 ‐ Dicarbonyl ‐ 3 ‐ ene, Produkte einer formalen Hydroacylierung der Dreifachbindung. Die Anwendungsbreite der Methode ist groß, verschiedene Arylsubstituenten an der Dicarbonyleinheit oder dem Alkin werden gut toleriert. Die Produkte können selektiv in Vinylchinoxaline überführt werden. Mechanistische Studien, inklusive Isotopenmarkierungsexperimente, weisen darauf hin, dass zunächst eine A3 ‐ Umsetzung zu Propargylaminen führt und eine darauffolgende basenvermittelte Alkin/Allen ‐ Umlagerung und eine Hydrolyse der Enaminteilstruktur während der Aufarbeitung das formale Hydroacylierungsprodukt liefern. Mit dem einfachen Katalysator AuCl und Piperidin liefern terminale Alkine und α ‐ Ketoaldehyde die Produkte einer formalen Hydroacylierung der Dreifachbindung mit ausgezeichneter Regio ‐ und Diastereoselektivität. Dies ist die erste goldkatalysierte Hydroacylierung; es gab keine Hinweise auf die klassischen A3 ‐ Kupplungsprodukte, die man in solch einer goldkatalysierten Reaktion eines Aldehyds, eines Amins und eines terminalen Alkins erwarten könnte. [ABSTRACT FROM AUTHOR]

Die enantioselektive Kreuzkupplung zwischen N ‐ Acylpyridinium ‐ Salzen und Organozinkreagentien nutzt ein Katalysatorsystem aus einer luftbeständigen Nickel(II) ‐ Quelle und einem chiralen Phosphoramiditliganden für die Synthese von 2 ‐ substituierten 2,3 ‐ Dihydro ‐ 4 ‐ pyridonen mit bis >99 % ee. [ABSTRACT FROM AUTHOR]

„Grand“iose Route: Ein Verfahren zur Überführung von 6 ‐ Acylcyclohexenonen in 2,6 ‐ disubstituierte 2,3,4,5 ‐ Tetrahydropyridine und, nach diastereoselektiver Reduktion, 2,6 ‐ syn ‐ disubstituierte Piperidine wurde entwickelt. Die Synthese von cis ‐ 2 ‐ Methoxycarbonylmethyl ‐ 6 ‐ pentylpiperidin und die erste Totalsynthese des Alkaloid (−) ‐ Grandisin G aus Elaeocarpus belegen die Anwendungsbreite dieser Methode. [ABSTRACT FROM AUTHOR]

γ-Butyrobetaine hydroxylase (BBOX) is a 2-oxoglutarate dependent oxygenase that catalyzes the final hydroxylation step in the biosynthesis of carnitine. BBOX was shown to catalyze the oxidative desymmetrization of achiral N, N-dialkyl piperidine-4-carboxylates to give products with two or three stereogenic centers. [ABSTRACT FROM AUTHOR]

Polymere Die dynamisch ‐ kovalente Chemie von 2,2,6,6 ‐ Tetramethylpiperidin ‐ 1 ‐ sulfanyl ‐ Dimeren aus einer thermisch reversiblen homolytischen Dissoziation von Disulfidbrücken wird von H. Otsuka et al. in der Zuschrift auf S. 2048 ff. beschrieben. [ABSTRACT FROM AUTHOR]