Synthesis Of Tetrahydropyrans Research Articles

Tetrahydropyran synthesis mediated by catalytic triflic acid and hexafluoroisopropanol

AbstractA Brønsted acid-catalyzed regioselective intramolecular hydroalkoxylation is described. This reaction proceeds via a carbocation intermediate and enables the preparation of 1,1,1’-trisubstituted tetrahydropyran derivatives under mild conditions using catalytic triflic acid (TfOH) and hexafluoroisopropanol (HFIP) as a mediator. Graphical abstract

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.

Changing the Reaction Pathway of Silyl-Prins Cyclization by Switching the Lewis Acid: Application to the Synthesis of an Antinociceptive Compound.

Developing new procedures for the synthesis of tetrahydropyrans in a very stereoselective manner is of great importance for the synthesis of THP-containing natural products. Here, we report an interesting protocol for the synthesis of polysubstituted halogenated tetrahydropyrans by silyl-Prins cyclization of vinylsilyl alcohols, in which the nature of the Lewis acid determines the outcome of the process. The methodology has been applied to the synthesis of a known antinociceptive.

Diastereoselective Synthesis of trans-β-Amino Cyclohexyl Ketones and trans-3-Amino-4-acyl-tetrahydropyrans from Intramolecular C-Alkylation of ω-Halo-Substituted β-Sulfinamido Ketones.

Reaction of ω-halo-substituted nonracemic β-sulfinamido ketones with NaH afforded the β-amino cyclohexyl ketones in excellent yields and diastereoselectivity, via an intramolecular C-alkylation, α to the carbonyl group. The reaction was found to be general and can be applied for the synthesis of different cyclohexyl amino ketones and tetrahydropyrans possessing amine and acyl substitutions.

Predicting Highly Enantioselective Catalysts Using Tunable Fragment Descriptors.

Catalyst optimization processes typically rely on inductive and qualitative assumptions of chemists based on screening data. While machine learning models using molecular properties or calculated 3D structures enable quantitative data evaluation, costly quantum chemical calculations are often required. In contrast, readily available binary fingerprint descriptors are time- and cost-efficient, but their predictive performance remains insufficient. Here, we describe a machine learning model based on fragment descriptors, which are fine-tuned for asymmetric catalysis and represent cyclic or polyaromatic hydrocarbons, enabling robust and efficient virtual screening. Using training data with only moderate selectivities, we designed theoretically and validated experimentally new catalysts showing higher selectivities in a challenging asymmetric tetrahydropyran synthesis.

Predicting Highly Enantioselective Catalysts Using Tunable Fragment Descriptors**

AbstractCatalyst optimization processes typically rely on inductive and qualitative assumptions of chemists based on screening data. While machine learning models using molecular properties or calculated 3D structures enable quantitative data evaluation, costly quantum chemical calculations are often required. In contrast, readily available binary fingerprint descriptors are time‐ and cost‐efficient, but their predictive performance remains insufficient. Here, we describe a machine learning model based on fragment descriptors, which are fine‐tuned for asymmetric catalysis and represent cyclic or polyaromatic hydrocarbons, enabling robust and efficient virtual screening. Using training data with only moderate selectivities, we designed theoretically and validated experimentally new catalysts showing higher selectivities in a challenging asymmetric tetrahydropyran synthesis.

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.

Large-Scale Synthesis of Chiral Tetrahydropyran via Asymmetric Allylation Catalyzed by (S)-3,3′-Cl2-BINOL

Large-Scale Synthesis of Chiral Tetrahydropyran via Asymmetric Allylation Catalyzed by (<i>S</i>)-3,3′-Cl₂-BINOL

Tandem Prins bicyclization for the synthesis of tetrahydropyran containing spirocompounds

A novel strategy has been developed for the synthesis of spiro compounds by the coupling of aldehydes with homoallylic alcohols derived from (±)-isopulegol with high selectivity in the presence of conventional Lewis acid BF3.OEt2 at −70 °C. This is the first report on the synthesis of mono-terpene fused spirotetrahydropyranyl derivatives. This method provides direct access to divergent spiro frameworks by Prins bicyclization.

Synthesis of fully functionalised spiropyran pyrazolone skeletons via a formal [4 + 2] cascade process using β-nitro-styrene-derived MBH-alcohols.

An efficient protocol was established to construct spiro pyrazolone tetrahydropyran scaffolds at ambient temperature under metal-free conditions. The reaction proceeded via formal [4 + 2] cyclisation of trans-β-nitro-styrene-derived Morita-Baylis-Hillman (MBH) alcohol with α-arylidene pyrazolone. The reaction followed an oxa-Michael/Michael cascade pathway, resulting in the formation of new C-C and C-O bonds. Organocatalytic synthesis of spiropyrazolones using quinine-derived catalyst resulted in 94% enantiomeric excess (ee) and excellent (>20 : 1) diastereoselectivity.

Prins cyclization-mediated stereoselective synthesis of tetrahydropyrans and dihydropyrans: an inspection of twenty years.

Functionalized tetrahydropyran (THP) rings are important building blocks and ubiquitous scaffolds in many natural products and active pharmaceutical ingredients (API). Among various established methods, the Prins reaction has emerged as a powerful technique in the stereoselective synthesis of the tetrahydropyran skeleton with various substituents, and the strategy has further been successfully applied in the total synthesis of bioactive macrocycles and related natural products. In this context, hundreds of valuable contributions have already been made in this area, and the present review is intended to provide the systematic assortment of diverse Prins cyclization strategies, covering the literature reports of the last twenty years (from 2000 to 2019), with an aim to give an overview on exciting advancements in this area and designing new strategies for the total synthesis of related natural products.

Organocatalytic diastereo- and enantioselective oxa-hetero-Diels-Alder reactions of enones with aryl trifluoromethyl ketones for the synthesis of trifluoromethyl-substituted tetrahydropyrans.

Tetrahydropyran derivatives are found in bioactives, and introduction of the trifluoromethyl group into molecules often improves biofunctions. Here we report diastereo- and enantioselective oxa-hetero-Diels-Alder reactions catalyzed by amine-based catalyst systems that afford trifluoromethyl-substituted tetrahydropyranones. Catalyst systems and conditions suitable for the reactions to provide the desired diastereomer products with high enantioselectivities were identified, and various trifluoromethyl-substituted tetrahydropyranones were synthesized with high diastereo- and enantioselectivities. Mechanistic investigation suggested that the reactions involve a [4 + 2] cycloaddition pathway, in which the enamine of the enone acts as the diene and the ketone carbonyl group of the aryl trifluoromethyl ketone acts as the dienophile. In this study, tetrahydropyran derivatives with the desired stereochemistry that are difficult to synthesize by previously reported methods were concisely obtained, and the range of tetrahydropyran derivatives that can be synthesized was expanded.

Mechanism of the Manolikakes Enamide-Based Domino Reaction for the Stereospecific Construction of Tetrahydropyrans.

The mechanism and stereoselectivity of the BF3-catalyzed, enamide-based domino reaction developed by Manolikakes et al. for tetrahydropyran synthesis have been studied using density functional theory calculations. All σ-bond formations were found to proceed through highly ordered cyclic or bicyclic transition states, leading to remarkable levels of diastereoselectivity. The role of the BF3 catalyst was demonstrated to be essential in both substrate activation and stereocontrol.

An Enamide-Based Domino Reaction for a Highly Stereoselective Synthesis of Tetrahydropyrans.

A novel method for the highly stereoselective synthesis of tetrahydropyrans is reported. This domino reaction is based on a twofold addition of enamides to aldehydes followed by a subsequent cyclization and furnishes fully substituted tetrahydropyrans in high yields. Three new σ‐bonds and five continuous stereogenic centers are formed in this one‐pot process with a remarkable degree of diastereoselectivity. In most cases, the formation of only one out of 16 possible diastereomers is observed. Two different stereoisomers can be accessed in a controlled fashion starting either from an E‐ or a Z‐configured enamide.

An Enamide‐Based Domino Reaction for a Highly Stereoselective Synthesis of Tetrahydropyrans

AbstractA novel method for the highly stereoselective synthesis of tetrahydropyrans is reported. This domino reaction is based on a twofold addition of enamides to aldehydes followed by a subsequent cyclization and furnishes fully substituted tetrahydropyrans in high yields. Three new σ‐bonds and five continuous stereogenic centers are formed in this one‐pot process with a remarkable degree of diastereoselectivity. In most cases, the formation of only one out of 16 possible diastereomers is observed. Two different stereoisomers can be accessed in a controlled fashion starting either from an E‐ or a Z‐configured enamide.

Inverse-Electron-Demand oxa-Diels-Alder Reactions of α-Keto-β,γ-unsaturated Esters and α,β-Unsaturated Hydrazones.

A concise synthetic method for dihydropyrans has been developed by inverse-electron-demand oxa-Diels-Alder reaction of α-keto-β,γ-unsaturated esters with α,β-unsaturated hydrazones as electron-rich olefins. This reaction is catalyzed by Eu(hfc)3 and proceeds in an endo-selective manner. This umpolung cycloaddition affords a variety of substituted dihydropyrans stereoselectively in high yields. In addition, indirect synthesis of formyl-substituted dihydropyran was achieved by dehydrazonation of the cycloadduct. This method is expected to be useful for the synthesis of dihydropyrans and tetrahydropyrans with unusual substitution patterns.

A Cooperative Hydrogen Bond Donor-Brønsted Acid System for the Enantioselective Synthesis of Tetrahydropyrans.

Carbocations stabilized by adjacent oxygen atoms are useful reactive intermediates involved in fundamental chemical transformations. These oxocarbenium ions typically lack sufficient electron density to engage established chiral Brønsted or Lewis acid catalysts, presenting a major challenge to their widespread application in asymmetric catalysis. Leading methods for selectivity operate primarily through electrostatic pairing between the oxocarbenium ion and a chiral counterion. A general approach to new enantioselective transformations of oxocarbenium ions requires novel strategies that address the weak binding capabilities of these intermediates. We demonstrate herein a novel cooperative catalysis system for selective reactions with oxocarbenium ions. This new strategy has been applied to a highly selective and rapid oxa-Pictet-Spengler reaction and highlights a powerful combination of an achiral hydrogen bond donor with a chiral Brønsted acid.

A Cooperative Hydrogen Bond Donor–Brønsted Acid System for the Enantioselective Synthesis of Tetrahydropyrans

AbstractCarbocations stabilized by adjacent oxygen atoms are useful reactive intermediates involved in fundamental chemical transformations. These oxocarbenium ions typically lack sufficient electron density to engage established chiral Brønsted or Lewis acid catalysts, presenting a major challenge to their widespread application in asymmetric catalysis. Leading methods for selectivity operate primarily through electrostatic pairing between the oxocarbenium ion and a chiral counterion. A general approach to new enantioselective transformations of oxocarbenium ions requires novel strategies that address the weak binding capabilities of these intermediates. We demonstrate herein a novel cooperative catalysis system for selective reactions with oxocarbenium ions. This new strategy has been applied to a highly selective and rapid oxa‐Pictet–Spengler reaction and highlights a powerful combination of an achiral hydrogen bond donor with a chiral Brønsted acid.

Organocatalytic Enantioselective Cycloetherifications Using a Cooperative Cation-Binding Catalyst.

A highly enantioselective cycloetherification strategy for the straightforward synthesis of enantioenriched tetrahydrofurans, tetrahydropyrans, and oxepanes using Song's cation-binding oligoEG catalyst and KF as the base is demonstrated. A wide range of ε-, ζ-, and η-hydroxy-α,β-unsaturated ketones were cyclized to the corresponding five-, six-, and seven-membered chiral oxacycles with high enantiopurity. This remarkably successful catalysis can be ascribed to systematic cooperative cation-binding catalysis in a densely confined supramolecular chiral cage generated in situ from the chiral catalyst, substrate, and KF.

Asymmetric Cycloetherification by Bifunctional Organocatalyst

Attempts to obtain enantiomerically enriched tetrahydrofuran derivatives via an intramolecular oxy-Michael addition reaction of ε-hydroxyenone is discussed. Despite previous difficulties associated with the asymmetric induction of this reaction, which can proceed even without a catalyst, a highly efficient asymmetric induction was realized using a bifunctional organocatalyst derived from a cinchona alkaloid. The reaction could be extended to ζ-hydroxyenone to yield an optically active tetrahydropyran derivative with a high ee. In these reactions, it is important for the gentle acidic and basic sites in the bifunctional organocatalyst to be arranged properly within the molecular skeleton of the catalyst. The high performance asymmetric induction relied on the affinity of the catalyst for the substrate, which played an important role. A disubstituted tetrahydropyran synthesis could be effectively performed via kinetic resolution using ζ-hydroxyenone containing a secondary alcohol moiety using a chiral phosphoric acid catalyst.