Saturated Heterocycles Research Articles

Vicinal stereocenters via asymmetric allylic alkylation and Cope rearrangement: a straightforward route to functionally and stereochemically rich heterocycles.

An asymmetric allylic alkylation/Cope rearrangement (AAA/[3,3]) capable of stereoselectively constructing vicinal stereocenters has been developed. Strategically integrated 4-methylation on the 3,3-dicyano-1,5-diene controls stereoselectivity and drives Cope rearrangement equilibrium in the forward direction. The AAA/[3,3] sequence rapidly converts abundant achiral and racemic starting materials into valuable (hetero)cycloalkane building blocks bearing significant functional and stereochemical complexity, highlighting the value of (hetero)cyclohexylidenemalononitriles as launching points for complex heterocycle synthesis. On this line, the resulting alkylidenemalononitrile moiety can be readily converted into amides via Hayashi-Lear amidation to ultimately yield amido-piperidines, tropanes, and related scaffolds with 3-5 stereocenters and drug-like functionality.

Chemoselective ring-opening metathesis polymerization of cyclopropenes spirally appended with N-aryl saturated heterocycles

The nature of the substituents on cyclopropenes and catalysts could have a profound effect on the reactivity and selectivity of ring-opening metathesis polymerization (ROMP).

Uncanonical Semireduction of Quinolines and Isoquinolines via Regioselective HAT-Promoted Hydrosilylation.

Heterocycles are the backbone of modern medical chemistry and drug development. The derivatization of "an olefin" inside aromatic rings represents an ideal approach to access functionalized saturated heterocycles from abundant aromatic building blocks. Here, we report an operationally simple, efficient, and practical method to selectively access hydrosilylated and reduced N-heterocycles from bicyclic aromatics via a key diradical intermediate. This approach is expected to facilitate complex heterocycle functionalizations that enable access to novel medicinally relevant scaffolds.

Chiral Lewis Acid-Catalyzed Norrish Type II Cyclization to Synthesize α-Oxazolidinones via Enantioselective Protonation

Chiral Lewis Acid-Catalyzed Norrish Type II Cyclization to Synthesize α-Oxazolidinones via Enantioselective Protonation

Radical Redox Annulations: A General Light-Driven Method for the Synthesis of Saturated Heterocycles.

We introduce here a two-component annulation strategy that provides access to a diverse collection of five- and six-membered saturated heterocycles from aryl alkenes and a family of redox-active radical precursors bearing tethered nucleophiles. This transformation is mediated by a combination of an Ir(III) photocatalyst and a Brønsted acid under visible-light irradiation. A reductive proton-coupled electron transfer generates a reactive radical which undergoes addition to an alkene. Then, an oxidative radical-polar crossover step leading to carbocation formation is followed by ring closure through cyclization of the tethered nucleophile. A wide range of heterocycles are easily accessible, including pyrrolidines, piperidines, tetrahydrofurans, morpholines, δ-valerolactones, and dioxanones. We demonstrate the scope of this approach through broad structural variation of both reaction components. This method is amenable to gram-scale preparation and to complex fragment coupling.

Visible Light-Mediated, Diastereoselective Epimerization of Morpholines and Piperazines to More Stable Isomers.

We report a photocatalyzed epimerization of morpholines and piperazines that proceeds by reversible hydrogen atom transfer (HAT) and provides an efficient strategy for editing the stereochemical configurations of these saturated nitrogen heterocycles, which are prevalent in drugs. The more stable morpholine and piperazine isomers are obtained from the more synthetically accessible but less stable stereoisomers, and a broad scope is demonstrated in terms of substitution patterns and functional group compatibility. The observed distributions of diastereomers correlate well with the relative energies of the diastereomer pairs as determined by density functional theory (DFT) calculations. Mechanistic studies, including luminescence quenching, deuterium labeling reactions, and determination of reversibility support a thiyl radical mediated HAT pathway for the epimerization of morpholines. Investigation of piperazine epimerization established that the mechanism is more complex and led to the development of thiol free conditions for the highly stereoselective epimerization of N,N'-dialkyl piperazines for which a previously unrecognized radical chain HAT mechanism is proposed.

Visible-light-Induced synthesis of imidazolidines through formal [3 + 2] cycloaddition of aromatic imines with N,N,N',N'-tetramethyldiaminomethane

Imidazolidine is a saturated heterocycle with a cyclic aminal core that can be used to develop new pharmacological drugs. Heteroleptic cyclometalated Ir(III) complex photosensitizers have been shown to enable the unprecedented synthesis of imidazolidines through a formal [3 + 2] photocycloaddition of aromatic imines with N,N,N',N'-tetramethyldiaminomethane. Herein, a reaction mechanism based on quenching experiments, quantum yield, ground-state redox potentials, and excited-state potentials is proposed.

Rhodium(CAAC)‐Catalyzed Arene Hydrogenation of Benzo‐Fused N‐Heterocycles to Saturated Building Blocks with an all‐cis Configuration

AbstractSaturated carbo‐ and heterocyclic building blocks can be readily obtained by the hydrogenation of aromatic carbo‐ and heterocycles. Although a variety of methods have been established to accomplish this transformation for simple arenes, the hydrogenation of aromatic N‐heterocycles is less explored. We herein report a diastereoselective arene hydrogenation which was applied to an array of benzo‐fused N‐heterocycles. A total of 48 saturated heterocycles was obtained by hydrogenation in the presence of the rhodium complex Cy(CAAC)Rh(cod)Cl in yields of 72–98% with moderate to high diastereoselectivities exhibiting the hydrogen atoms in an all‐cis arrangement. The high tolerance towards functional groups enables the formation of valuable saturated products, which offer a starting point for further derivatization.magnified image

Diverse saturated heterocycles from a hydroacylation/conjugate addition cascade.

Rhodium-catalyzed hydroacylation using alkynes substituted with pendant nucleophiles, delivers linear α,β-unsaturated enone intermediates with excellent regioselectivity. These adducts are used to construct a broad range of diversely substituted, saturated O-, N- and S-heterocycles in a one-pot process. Judicious choice of cyclisation conditions enabled isolation of O-heterocycles with high levels of diastereoselectivity. A variety of derivatisation reactions are also performed, generating functionalised hydroacylation products. This sequence serves as a general approach for the synthesis of fully saturated heterocycles.

Functionalisation of ethereal-based saturated heterocycles with concomitant aerobic C-H activation and C-C bond formation.

With an ever-growing emphasis on sustainable synthesis, aerobic C–H activation (the use of oxygen in air to activate C–H bonds) represents a highly attractive conduit for the development of novel synthetic methodologies. Herein, we report the air mediated functionalisation of various saturated heterocycles and ethers via aerobically generated radical intermediates to form new C–C bonds using acetylenic and vinyl triflones as radical acceptors. This enables access to a variety of acetylenic and vinyl substituted saturated heterocycles that are rich in synthetic value. Mechanistic studies and control reactions support an aerobic radical-based C–H activation mechanism.

Chemoselective and Tandem Reduction of Arenes Using a Metal-Organic Framework-Supported Single-Site Cobalt Catalyst.

The development of heterogeneous, chemoselective, and tandem catalytic systems using abundant metals is vital for the sustainable synthesis of fine and commodity chemicals. We report a robust and recyclable single-site cobalt-hydride catalyst based on a porous aluminum metal-organic framework (DUT-5 MOF) for chemoselective hydrogenation of arenes. The DUT-5 node-supported cobalt(II) hydride (DUT-5-CoH) is a versatile solid catalyst for chemoselective hydrogenation of a range of nonpolar and polar arenes, including heteroarenes such as pyridines, quinolines, isoquinolines, indoles, and furans to afford cycloalkanes and saturated heterocycles in excellent yields. DUT-5-CoH exhibited excellent functional group tolerance and could be reusable at least five times without decreased activity. The same MOF-Co catalyst was also efficient for tandem hydrogenation-hydrodeoxygenation of aryl carbonyl compounds, including biomass-derived platform molecules such as furfural and hydroxymethylfurfural to cycloalkanes. In the case of hydrogenation of cumene, our spectroscopic, kinetic, and density functional theory (DFT) studies suggest the insertion of a trisubstituted alkene intermediate into the Co-H bond occurring in the turnover limiting step. Our work highlights the potential of MOF-supported single-site base-metal catalysts for sustainable and environment-friendly industrial production of chemicals and biofuels.

Transaminase Catalysis for Enantiopure Saturated Heterocycles as Potential Drug Scaffolds

As efforts in rational drug design are driving the pharmaceutical industry towards more complex molecules, the synthesis and production of these new drugs can benefit from new reaction routes. In addition to the introduction of new centers of asymmetry, complexity can be also increased by ring saturation, which also provides improved developability measures. Therefore, in this report, our aim was to develop transaminase (TA)-catalyzed asymmetric synthesis of a new group of potential chiral drug scaffolds comprising a saturated amine heterocycle backbone and an asymmetric primary amine sidechain (55a–g). We screened the Codex® Amine Transaminase Kit of 24 transaminases with the morpholine containing ketone 57a, resulting in one (R)-selective TA and three (S)-selective TAs operating at 100 mM substrate concentration and 25 v/v% isopropylamine (IPA) content. The optimized reaction conditions were than applied for asymmetric transamination of further six ketones (57b–g) containing various amine heterocycles, in which a strong effect of the substitution pattern of the γ-position relative to the substituted N-atom could be observed. Mediated by the most enantiotope selective (S)-TAs in scaled-up process, the (S)-amines [(S)-55a–g] were isolated with moderate-to-excellent yields (47–94%) in enantiopure form (>99% ee).

Cascade Ring-Opening Dual Halogenation of Cyclopropenones with Saturated Oxygen Heterocycles.

Represented is a CuX2- or I2-promoted ring-opening dual halogenation of cyclopropenones with saturated oxygen heterocycles, providing an efficient method for the synthesis of 3-haloacrylates. The ring-opening reaction enables the construction of two C-X (X = Cl, Br, or I) bonds and a C-O bond as well as the cleavage of two C-O bonds and a C-C bond in a single step. This protocol is highly atom economical, has an excellent substrate scope, and exhibits the ability for gram-scale reaction.

Regio- and Stereoselective Alkylboration of Endocyclic Olefins Enabled by Nickel Catalysis.

Whereas there is a significant interest in the rapid construction of diversely substituted saturated heterocycles, direct and modular access is currently limited to the mono-, 2,3-, or 3,4-substitution pattern. This Communication describes the straightforward and modular construction of 2,4-substituted saturated heterocycles from readily available materials in a highly stereo- and regioselective manner, which sets the stage for numerous readily accessible drug motifs. The strategy relies on chain walking catalysis.

Experimental study and molecular simulation on aggregation behavior of surface‐active ionic liquids containing saturated nitrogen heterocycles in aqueous solution

AbstractThe aggregation behavior of N‐decyl‐N‐methylmorpholinium bromide (DMMB) in aqueous solutions was systematically investigated by experimental measurements and molecular simulation, including surface tension, electrical conductivity, fluorescence measurement, 1H NMR and dissipative particle dynamic (DPD) simulation. The critical micelle concentration (cmc) of DMMB which was obtained by different techniques showed a pretty good agreement. From the surface tension measurements, a series of surface adsorption properties such as surface tension at the cmc (γcmc), effectiveness of surface tension reduction (∏cmc), maximum surface excess concentration (Γmax), minimum surface area per molecule (Amin), were determined. The cmc values and a variety of thermodynamic parameters (, and ) of micellization in the temperature range of 25–45°C were obtained via electrical conductivity experiments. In the investigated temperature range, the thermodynamic parameters reveal that micelle formation is entropy‐driven. Furthermore, micelle aggregation number (Nagg) of DMMB was calculated through the fluorescence measurement. Analysis of the 1H NMR spectrum indicates the micelle formation mechanism. The DPD simulation reflects the process of micro‐phase separation. From the simulation results, at concentrations higher than cmc, spherical micelles can be formed. The investigation of DMMB micelles may help us gain a better understanding about surfactant micellization process and expand the range of potential application in materials science.

Light rearranges rings

Chemists have become adept at changing the groups on the periphery of molecules, sort of like moving around decorations on a mantlepiece. But changing a molecule’s core scaffolding is more challenging. Researchers have now discovered a way to rearrange molecular cores by turning certain six-membered rings into five-membered rings. The transformation could be used to alter the skeletons of molecules, including pharmaceuticals and agrochemicals, into novel structures. Visible light powers the novel ring-contraction reaction, which University of California, Berkeley, graduate student Justin Jurczyk presented last week at American Chemical Society Fall 2021. The reaction converts saturated heterocycles with six atoms, including cyclic amines, ethers (example shown), and thioethers, into five-carbon rings with pendant amines, alcohols, or thiols, respectively. “We’re not adding any atoms; we’re not deleting any atoms,” Jurczyk told C&EN. “We’re really just rearranging where they are in space.” UC Berkeley’s Richmond Sarpong , who led the research effort

Discovery and evaluation of non-basic small molecule modulators of the atypical chemokine receptor CXCR7

The atypical chemokine receptor C–X–C chemokine receptor type 7 (CXCR7) is an attractive therapeutic target for a variety of cardiac and immunological diseases. As a strategy to mitigate known risks associated with the development of higher molecular weight, basic compounds, a series of pyrrolidinyl-azolopyrazines were identified as promising small-molecule CXCR7 modulators. Using a highly enabled parallel medicinal chemistry strategy, structure–activity relationship studies geared towards a reduction in lipophilicity and incorporation of saturated heterocycles led to the identification of representative tool compound 20. Notably, compound 20 maintained good potency against CXCR7 with a suitable balance of physicochemical properties to support in vivo pharmacokinetic studies.

Sonogashira Cross‐Coupling Reaction of Bromocyanofluoro Pyridine Compounds: Access to 5‐ and 6‐Alkynylfluoropyridinamidoximes Scaffolds

AbstractWe disclose a general two‐step procedure to access hitherto unknown and under explored 5‐ and 6‐alkynyl‐3‐fluoro‐2‐pyridinamidoximes from 5‐ and 6‐bromo‐3‐fluoro‐2‐cyanopyridines and a wide range of easily available and bench‐stable terminal alkynes, using Sonogashira cross‐coupling, as the first step. The generation of the polar amidoxime group is realized at a late stage upon treatment of the alkynylfluorocyanopyridine by hydroxylamine. This mild and operationally simple two‐step room temperature process is compatible with enantiopure chiral substrates and various functionality including free alcohols, unprotected and CBz‐protected amines, acetonides, benzyl ethers, amide, imide, di‐substituted alkynes and strained saturated heterocycles.

Photomediated ring contraction of saturated heterocycles.

Saturated heterocycles are found in numerous therapeutics and bioactive natural products and are abundant in many medicinal and agrochemical compound libraries. To access new chemical space and function, many methods for functionalization on the periphery of these structures have been developed. Comparatively fewer methods are known for restructuring their core framework. Herein, we describe a visible light-mediated ring contraction of α-acylated saturated heterocycles. This unconventional transformation is orthogonal to traditional ring contractions, challenging the paradigm for diversification of heterocycles including piperidine, morpholine, thiane, tetrahydropyran, and tetrahydroisoquinoline derivatives. The success of this Norrish type II variant rests on reactivity differences between photoreactive ketone groups in specific chemical environments. This strategy was applied to late-stage remodeling of pharmaceutical derivatives, peptides, and sugars.

Azetidines of pharmacological interest.

Azetidines are almost unexplored among nitrogen-containing saturated heterocycles due to difficulties associated with their synthesis. However, over the past few years, attempts have been made by scientists to advance their synthetic feasibility. Compounds with the azetidine moiety display an important and diverse range of pharmacological activities, such as anticancer, antibacterial, antimicrobial, antischizophrenic, antimalarial, antiobesity, anti-inflammatory, antidiabetic, antiviral, antioxidant, analgesic, and dopamine antagonist activities, and are also useful for the treatment of central nervous system disorders and so forth. Owing to its satisfactory stability, molecular rigidity, and chemical and biological properties, azetidine has emerged as a valuable scaffold and it has drawn the attention of medicinal researchers. The present review sheds light on the traditional method of synthesis of azetidine and advancements in synthetic methodology over the past few years, along with its application with various examples, and its biological significance.