Tetrahydropyran Research Articles

Nano Fe3O4 catalyzed selective, tandem, and oxidative conversion of alcohols, tetrahydropyranyl and trimethylsilyl ethers to oximes

Tandem and efficient conversion of alcohols, tetrahydropyranyl (THP) and trimethylsilyl (TMS) ethers as protected alcohols to oximes is described using a catalytic amount of nano Fe3O4 as a highly magnetic and nontoxic catalyst, tert-butyl hydroperoxide (TBHP) and hydroxylamine hydrochloride. The nanocatalyst is easily separated from the reaction medium using an external magnet and can be reused for several times without any considerable loss of its catalytic power. Also, it was found that it is possible to perform these oxidative conversions efficiently even in the presence of epoxides, carboxylic acids and esters, phenols, sulfides and pyridine rings with excellent chemoselectivity. The tandem and catalytic nature, catalyst reusability, high yields, and easy work up can be considered as the main advantages of the present environmentally friendly method.

Tuning the Solvation Structure of a Weakly Solvating Cyclic Ether Electrolyte for Wide‐Temperature Cycling of Lithium‐Sulfurized Polyacrylonitrile Batteries

AbstractSulfurized polyacrylonitrile (SPAN) cathodes in high energy‐density Li‐metal batteries have garnered widespread interest owing to their good cycling stability and moderately high capacities. However, their application is hindered by the low prevalence of advanced electrolytes that can simultaneously mitigate polysulfide generation at the cathode and stabilize the Li‐metal anode. Here, a weakly solvating electrolyte is presented, employing a single solvent tetrahydropyran (THP). The solvation structure is effectively tuned by adjusting the salt concentration to stabilize both the Li‐metal anode and SPAN cathode. This approach enables stable cycling with high SPAN loadings (≈5 mg cm−2) and lean electrolyte contents (≈5 µL mgSPAN−1) across a wide temperature range: 0 °C, room temperature, and 50 °C. A pouch cell with a high SPAN loading and a low electrolyte‐to‐SPAN (E/SPAN) ratio of 3 µL mg−1 shows a stable 79.1% capacity retention after 40 cycles. Additionally, THP can be effectively employed in localized high‐concentration electrolyte (LHCE) systems to reduce the diluent‐to‐solvent ratio for greater LHCE viability. The study demonstrates the potential of weakly solvating solvents in Li‐SPAN batteries, offering a pathway for their practical application.

An Integrated Module Performs Selective 'Online' Epoxidation in the Biosynthesis of the Antibiotic Mupirocin.

The delineation of the complex biosynthesis of the potent antibiotic mupirocin, which consists of a mixture of pseudomonic acids (PAs) isolated from Pseudomonas fluorescens NCIMB 10586, presents significant challenges, and the timing and mechanisms of several key transformations remain elusive. Particularly intriguing are the steps that process the linear backbone from the initial polyketide assembly phase to generate the first cyclic intermediate PA-B. These include epoxidation as well as incorporation of the tetrahydropyran (THP) ring and fatty acid side chain required for biological activity. Herein, we show that the mini-module MmpE performs a rare online (ACP-substrate) epoxidation and is integrated ('in-cis') into the polyketide synthase via a docking domain. A linear polyketide fragment with six asymmetric centres was synthesised using a convergent approach and used to demonstrate substrate flux via an atypical KS0 and a previously unannotated ACP (MmpE_ACP). MmpE_ACP-bound synthetic substrates were critical in demonstrating successful epoxidation in vitro by the purified MmpE oxidoreductase domain. Alongside feeding studies, these results confirm the timing as well as chain length dependence of this selective epoxidation. These mechanistic studies pinpoint the location and nature of the polyketide substrate prior to the key formation of the THP ring and esterification that generate PA-B.

Water‐Lean Inner Helmholtz Plane Enabled by Tetrahydropyran for Highly Reversible Zinc Metal Anode

AbstractThe reversibility and stability of zinc (Zn) metal anode are closely related to inner Helmholtz plane (IHP) chemistry. The H2O‐rich IHP raises severe parasitic reactions and irregular Zn deposition, impeding the practical utility of Zn anode in aqueous Zn‐ion batteries (AZIBs). In this study, tetrahydropyran (THP), a five‐carbon heterocyclic ether with permanent dipole moment and hydrophobic characteristic, is introduced as a self‐adsorptive additive to reshape the IHP. It squeezes out partial H2O molecules and forms a H2O‐lean IHP, benefitting for alleviating active H2O decomposition and improving the stability of Zn anode. Moreover, the adsorbed THP induces the preferential nucleation of Zn (002) plane, facilitating dendrite‐free growth and improving the reversibility of Zn anode. Consequently, the Zn||Zn symmetric cell enables to cycle over 3600 h at 5 mA cm−2@ 1 mAh cm−2. The Zn||Cu half‐cell can stably cycle over 400 cycles with 99.9% coulombic efficiency even under harsh test conditions (10 mA cm−2@5 mAh cm−2) with 30 µm Zn foil. The Zn||NH4V4O10 full cell maintains 92.6% capacity retention after 800 cycles at 1 A g−1 and the Zn||I2 full cell enables to perform steadily over 10000 cycles with a capacity decay rate of merely 0.003% per cycle at 5 C.

An Integrated Module Performs Selective ‘On‐Line’ Epoxidation in the Biosynthesis of the Antibiotic Mupirocin.

The delineation of the complex biosynthesis of the potent antibiotic mupirocin, which consists of a mixture of pseudomonic acids (PAs) isolated from Pseudomonas fluorescens NCIMB 10586, presents significant challenges and the timing and mechanisms of several key transformations remain elusive. Particularly intriguing are the steps that process the linear backbone from the initial polyketide assembly phase to generate the first cyclic intermediate PA‐B. These include epoxidation as well as incorporation of the tetrahydropyran (THP) ring and fatty acid sidechain required for biological activity. Here, we show that the mini‐module MmpE performs a rare online (ACP‐substrate) epoxidation and is integrated (‘in‐cis’) into the polyketide synthase via a docking domain. A linear polyketide fragment with 6 asymmetric centres was synthesised using a convergent approach and used to demonstrate substrate flux via an atypical KS0 and a previously unannotated ACP (MmpE_ACP). MmpE_ACP‐bound synthetic substrates were critical in demonstrating successful epoxidation in vitro by the purified MmpE oxidoreductase domain. Alongside feeding studies, these results confirm the timing as well as chain length dependence of this selective epoxidation. These mechanistic studies pinpoint the location and nature of the polyketide substrate prior to the key formation of the THP ring and esterification that generate PA‐B.

A Weakly Solvating Ether Electrolyte Enables Fast-Charging and Wide-Temperature Lithium-Ion Pouch Cells.

Graphite-based lithium-ion batteries have succeeded greatly in the electric vehicle market. However, they suffer from performance deterioration, especially at fast charging and low temperatures. Traditional electrolytes based on carbonated esters have sluggish desolvation kinetics, recognized as the rate-determining step. Here, a weakly solvating ether electrolyte with tetrahydropyran (THP) as the solvent is designed to enable reversible and fast lithium-ion (Li+) intercalation in the graphite anode. Unlike traditional ether-based electrolytes which easily cointercalate into the graphite layers, the THP-based electrolyte shows fast desolvation ability and can match well with the graphite anode. In addition, the weak interconnection between Li+ and THP allows more anions to come into the solvating shell of Li+, inducing an inorganic-rich interface and thus suppressing the side reactions. As a result, the lithium iron phosphate/graphite pouch cell (3 Ah) with the THP electrolyte shows a capacity retention of 80.3% after 500 cycles at 2 C charging, much higher than that of the ester electrolyte system (7.6% after 200 cycles). At 4 C charging, the discharging capacity is increased from 2.29 Ah of esters to 2.96 Ah of THP. Furthermore, the cell can work normally over wide working temperatures (-20 to 60 °C). Our electrolyte design provides some understanding of lithium-ion batteries at fast charging and wide temperatures.

Stereoselective Synthesis of Polysubstituted Tetrahydropyrans by Brønsted Acid‐Mediated Hydroxyalkoxylation of Silylated Alkenols

AbstractA convenient route for the preparation of tetrahydropyran (THP) derivatives with a quaternary and tertiary vicinal stereocenters is reported. The atom economy acid‐catalyzed cyclization of allylsilyl alcohols provided polysubstituted tetrahydropyrans in good yields and excellent diastereoselectivities (>95 : 5). In comparison with the traditional oxymercuration procedure, this approach resulted to be more efficient in both yield and stereocontrol.

The chromosome-scale assembly of the Notopterygium incisum genome provides insight into the structural diversity of coumarins

Coumarins, derived from the phenylpropanoid pathway, represent one of the primary metabolites found in angiosperms. The alignment of the tetrahydropyran (THP) and tetrahydrofuran (THF) rings with the lactone structure results in the formation of at least four types of complex coumarins. However, the mechanisms underlying the structural diversity of coumarin remain poorly understood. Here, we report the chromosome-level genome assembly of Notopterygium incisum, spanning 1.64 Gb, with a contig N50 value of 22.7 Mb and 60,021 annotated protein-coding genes. Additionally, we identified the key enzymes responsible for shaping the structural diversity of coumarins, including two p-coumaroyl CoA 2′-hydroxylases crucial for simple coumarins basic skeleton architecture, two UbiA prenyltransferases responsible for angular or linear coumarins biosynthesis, and five CYP736 cyclases involved in THP and THF ring formation. Notably, two bifunctional enzymes capable of catalyzing both demethylsuberosin and osthenol were identified for the first time. Evolutionary analysis implies that tandem and ectopic duplications of the CYP736 subfamily, specifically arising in the Apiaceae, contributed to the structural diversity of coumarins in N. incisum. Conclusively, this study proposes a parallel evolution scenario for the complex coumarin biosynthetic pathway among different angiosperms and provides essential synthetic biology elements for the heterologous industrial production of coumarins.

Diluent modified weakly solvating electrolyte for fast-charging high-voltage lithium metal batteries

Weakly solvating electrolyte (WSE) demonstrates superior compatibility with lithium (Li) metal batteries (LMBs). However, its application in fast-charging high-voltage LMBs is challenging. Here, we propose a diluent modified WSE for fast-charging high-voltage LMBs, which is formed by adding diluent of 1,1,2,2-tetrafluoroethyl-2,2,3,3-tetrafluoropropyl ether (TTE) into the tetrahydropyran (THP) based WSE. A relatively loose solvation structure is formed due to the formation of weak hydrogen bond between TTE and THP, which accelerates the de-solvation kinetics of Li+. Besides, more anions are involved in solvation structure in the presence of TTE, yielding inorganic-rich interphases with improved stability. Li (30 µm)||LiNi0.5 Co0.2Mn0.3O2 (4.1 mAh/cm2) batteries with the TTE modified WSE retain over 64 % capacity retention after 175 cycles under high rate of 3 C and high-voltage of 4.5 V, much better than that with pure THP based WSE. This work points out that the combination of diluent with weakly solvating solvent is a promising approach to develop high performance electrolytes for fast-charging high-voltage LMBs.

Brønsted acid-mediated selective α-alkenylation of 3,4-dihydro-2H-pyrans

A protocol for the synthesis of α-alkenylated tetrahydropyrans (THPs) with 3,4-dihydro-2H-pyran derivatives and potassium alkenyltrifluoroborates was achieved in the presence of a Brønsted acid and a Lewis acid under mild reaction conditions.

Combining total synthesis and genetic engineering to probe dihydropyran formation in ambruticin biosynthesis.

The ambruticins are a family of potent antifungal polyketide derived natural products isolated from the myxobacterium Sorangium cellulosum. Their unusual structures include a trisubstituted cyclopropyl group and two oxygen heterocycles, a tetrahydropyran (THP) and dihydropyran (DHP). Herein we report a flexible modular approach for the total synthesis of ambruticins which is used to prepare ambruticins F and S as well as in the first total synthesis of 20,21-dihydroambruticin F. The flexible strategy unites 3 fragments via Julia-Kocienski olefinations and provides important standards for investigation of dihydropyran formation in ambruticin biosynthesis. Cultures of wild-type S. cellulosum So ce10 produce mainly ambruticin S and the VS series of metabolites. An efficient electroporation method enabled gene knockout experiments which revealed that the ΔambP-S mutant of S. cellulosum accumulated the bisTHP polyketide 20,21-dihydroambruticin F. In contrast, the ΔambN-S mutant gave ambruticin F with the 20,21-alkene as the major metabolite confirming that AmbP and AmbO (a Rieske enzyme and flavin-dependent monooxygenase respectively) are implicated in 20,21-alkene formation. The results of feeding studies to a Sorangium strain containing only ambP and ambO are in accord with formation of the 20,21-alkene occurring prior to generation of the C3 to C7 dihydroxylated tetrahydropyran in ambruticin biosynthesis.

Harnessing the 1,3-azadiene-anhydride reaction for the regioselective and stereocontrolled synthesis of lactam-fused bromotetrahydropyrans by bromoetherification of lactam-tethered trisubstituted tertiary alkenols.

Halo-cycloetherification of lactam-tethered alkenols enables the construction of oxygen-heterocycles that are fused to nitrogen heterocycles via intramolecular halonium-induced nucleophilic addition. Specifically, tetrahydropyrans (THPs) that are fused to a nitrogen heterocycle constitute the core of several bioactive molecules, including tachykinin receptor antagonists and alpha-1 adrenergic antagonists. Although the literature is replete with successful examples of the halo-cycloetherification of simple mono- or disubstituted primary alkenols, methods for the modular, efficient, regioselective, and stereocontrolled intramolecular haloetherification of sterically encumbered trisubstituted tertiary alkenols are rare. Here, we describe a simple intramolecular bromoetherification strategy that meets these benchmarks and proceeds with exclusive 6-endo regioselectivity. The transformation employs mild and water-tolerant conditions, which bodes well for late-stage diversification. The hindered ethers contain four contiguous stereocenters as well as one halogen-bearing tetrasubstituted stereocenter.

Pyrrolopyrimidine based CSF1R inhibitors: Attempted departure from Flatland

The colony-stimulating factor 1 receptor (CSF1R) is an attractive target for inflammation disorders and cancers. Based on a series of pyrrolo[2,3-d]pyrimidine containing two carbo-aromatic rings, we have searched for new CSF1R inhibitors having a higher fraction of sp3-atoms. The phenyl unit in the 4-amino group could efficiently be replaced by tetrahydropyran (THP) retaining inhibitor potency. Exchanging the 6-aryl group with cyclohex-2-ene units also resulted in highly potent compounds, while fully saturated ring systems at C-6 led to a loss of activity. The structure-activity relationship study evaluating THP containing pyrrolo[2,3-d]pyrimidine derivates identified several highly active inhibitors by enzymatic studies. A comparison of 11 pairs of THP and aromatic compounds showed that inhibitors containing THP had clear benefits in terms of enzymatic potency, solubility, and cell toxicity. Guided by cellular experiments in Ba/F3 cells, five CSF1R inhibitors were further profiled in ADME assays, indicating the para-aniline derivative 16t as the most attractive compound for further development.

The effect of the active site and substrate structure in preparation of substituted tetrahydropyrans via intramolecular cyclization

Substituted tetrahydropyrans (THPs) are important biologically active compounds and synthetic intermediates. Their prevalence and diverse applications make them desirable targets in synthetic organic chemistry. Current synthetic routes for THP synthesis involve homogeneous catalysts and usually multiple steps and the use of expensive heavy metal catalysts, which pose environmental concerns. Therefore, there is a need for alternative approaches that can enhance efficiency, eco-friendliness, and cost-effectiveness This study focuses on the acid-catalyzed synthesis of THPs through the intramolecular cyclization of substituted (E)− 5-phenylpent-4-en-1-ols over zeolites as heterogeneous catalysts. The study particularly focused on investigating the influence of functional groups, as well as substrate size, on the reaction outcome. The results demonstrated that electron-donating groups enhance the conversion of the reactants and increase selectivity towards THPs, while electron-withdrawing groups have the opposite effect. Furthermore, the cyclization reaction also occurred on substrates containing different aromatic cycles. However, the conversion of a bulky substrate containing naphthyl group decreased due to mass transfer limitations. The catalytic performance of different types of zeolites with diverse acid sites was also examined. Brønsted acidic zeolites such as Al-BEA and Ga-BEA exhibited promising catalytic performance and 94 % and 83 % selectivity towards THPs, respectively. In contrast, Lewis acidic zeolites such as Sn-BEA, Ti-BEA, and Zr-BEA showed conversions below 6.5 % and poor selectivity, showing that Brønsted acidic zeolites are more suitable for the cyclization reaction than Lewis acidic zeolites.

Catalytic Enantioselective Intramolecular Oxa-Michael Reaction to α,β-Unsaturated Esters and Amides.

A bifunctional iminophosphorane (BIMP)-catalyzed, enantioselective intramolecular oxa-Michael reaction of alcohols to tethered, low electrophilicity Michael acceptors is described. Improved reactivity over previous reports (1 day vs 7 days), excellent yields (up to 99%), and enantiomeric ratios (up to 99.5:0.5 er) are demonstrated. The broad reaction scope, enabled by catalyst modularity and tunability, includes substituted tetrahydrofurans (THFs) and tetrahydropyrans (THPs), oxaspirocycles, sugar and natural product derivatives, dihydro-(iso)-benzofurans, and iso-chromans. A state-of-the-art computational study revealed that the enantioselectivity originates from the presence of several favorable intermolecular hydrogen bonds between the BIMP catalyst and the substrate that induce stabilizing electrostatic and orbital interactions. The newly developed catalytic enantioselective approach was carried out on multigram scale, and multiple Michael adducts were further derivatized to an array of useful building blocks, providing access to enantioenriched biologically active molecules and natural products.

Weakly Solvating Cyclic Ether Electrolyte for High-Voltage Lithium Metal Batteries

The commercialization of high-voltage lithium (Li) metal batteries (LMBs) has been severely hindered due to the lack of advanced electrolytes that can simultaneously support a stable lithium metal anode (LMA) and high-voltage cathode (>4 V vs Li+/Li). Here, we propose a tetrahydropyran (THP)-based weakly solvating electrolyte (WSE) to regulate Li+ solvation structures and interfacial behaviors. The anion-rich Li+ solvation in THP-based WSE effectively promotes the formation of inorganic-rich solid electrolyte interphase (SEI) layers, firm cathode electrolyte interphase (CEI) films, and protective passivation films on an Al current collector. The optimized interfacial behaviors contribute to the highly compact Li deposition, high-voltage stability, and inhibition of transition metal ion dissolution and Al corrosion. Finally, the Li||LiNi0.5Co0.2Mn0.3O2 full cell delivered stable cycling performance at high cutoff voltages of 4.3 and even 4.5 V. This study demonstrates an exciting approach to enable ether-based electrolytes for high-voltage LMBs and could be developed for other battery systems.

Thermally Induced Phase Transition of Cubic Structure II Hydrate: Crystal Structures of Tetrahydropyran–CO2 Binary Hydrate

We report a thermally induced phase transition of cubic structure II hydrates of tetrahydropyran (THP) and CO2 below about 140 K. The phase transition was characterized by powder X-ray diffraction measurements at variable temperatures. A dynamical ordering of the CO2 guests in small pentagonal dodecahedral 512 host water cages, not previously observed in the simple CO2 hydrate, occurs simultaneously with the symmetry lowering transition from a cubic structure II (space group Fd-3m with cell dimensions a = 17.3202(7) Å at 153 K) to a tetragonal (space group I41/amd with cell dimensions a = 17.484(4) Å and c = 12.145(1) Å at 138 K) unit cell. The effect of guest molecules on the phase transition at low temperatures is discussed, which demonstrates that the clathrate hydrate structures and thermodynamic properties can be modified by adjusting the size and chemical structure of larger and smaller guest molecules.

Continuous hydrate-based CO2 separation from H2 + CO2 gas mixture using cyclopentane as co-guest

CO2 separation from H2 + CO2 gas mixture is a necessary technology for a stable supply of blue hydrogen. Among CO2 separation technology, hydrate-based CO2 separation is an environmentally and economically superior technology. Cyclopentane (CP) was selected as guest compound to enable hydrate-based CO2 separation under thermodynamic conditions closer to normal pressure and temperature. Hydrate-based continuous CO2 separation experiments are conducted in the H2 + CO2 + CP + H2O system at 284 K. The results of these experiments showed that mole fraction of H2 in the gas phase reached 0.9 at the steady state in the H2 + CO2 + CP + H2O system after the CO2 was extracted via hydrate formation. At the same time, more H2 was incorporated into the mixed hydrate during this process as the concentration of H2 in the gas phase increases post hydrate formation. Therefore, it was demonstrated that hydrate-based CO2 separation was successful in H2 + CO2 + CP + H2O system at 284 K but there is also increase of energy costs caused by H2 loss. The PXRD results identified H2 + CO2 + CP hydrate as structure II hydrate. Although H2 + CO2 + Tetrahydropyran (THP) hydrate also forms structure II hydrate, more H2 is encapsulated in the H2 + CO2 + CP mixed hydrate than in the H2 + CO2 + THP mixed hydrate. This difference may be caused by the difference in the lattice constants of CP and THP hydrates, which arises from the difference in molecular size of CP and THP, from the differences between the large guest–host interactions, and from differences arising from hydrogen bonding of THP with the host water framework which can decrease the H2 holding capacity. In this study, it was revealed that the molecular diameter of the guest molecules need also to be considered in addition to the phase equilibrium conditions of the hydrates when selecting guest compound of hydrates.

Preparation of functionalised tetrahydropyrans catalysed by isoreticular zeolites

Synthetic organic chemistry targets functionalised tetrahydropyrans (THP) for their large number of biologically active compounds. However, synthetic routes for THPs commonly require multiple, time-consuming steps and/or expensive and environmentally unfriendly catalysts. In this context, we tested zeolites as inexpensive, eco-friendly, thermostable, shape-selective, and industrially relevant catalysts for THP synthesis. Herein, we report the synthesis of 2-phenyltetrahydropyran by (E)-5-phenylpent-4-en-1-ol cyclisation over a set of isoreticular IPC-n zeolites prepared by Assembly-Disassembly-Organisation-Reassembly (ADOR) transformation from a UTL parent material and over commercially available H-BEA catalysts. The results showed that, regardless of zeolite structure, the cyclisation reaction favours the formation of 2-phenyltetrahydropyran as the main product and that reactant conversion and kinetics depend on the total number of acid sites. By contrast, textural properties do not significantly affect conversion or selectivity. Thus, our approach illustrates a facile, inexpensive, and environmentally friendly method for the synthesis of tetrahydropyrans by cyclisation reaction using zeolites as catalysts.

A Mild, Efficient and Sustainable Tetrahydropyranylation of Alcohols Promoted by Acidic Natural Deep Eutectic Solvents.

A straightforward protocol to promote the tetrahydropyranylation of alcohols, using for the first time bioinspired acidic natural deep eutectic solvents (NADESs) as non-innocent reaction media under mild reaction conditions, was reported. This approach enables the preparation of several tetrahydropyranyl (THP) ethers starting from primary, secondary and tertiary alcohols in short reaction times and with high levels of chemoselectivity, working under air and without the need of additional catalyst. The sustainability of the methodology was further highlighted by its scalability and the easy recyclability of the NADES, allowing multigram preparations of THP ethers without any loss of the catalytic activity of the reaction media up to ten recycling steps. Telescoped, one-pot tetrahydropyranylation/nucleophilic acyl substitution transformations using the same eutectic mixture were also demonstrated.