Synthesis Of Γ-lactones Research Articles

Stereodivergent Synthesis of 1,4-Dicarbonyl Compounds through Sulfonium Rearrangement: Mechanistic Investigation, Stereocontrolled Access to γ-Lactones and γ-Lactams, and Total Synthesis of Paraconic Acids.

Although simple γ-lactones and γ-lactams have received considerable attention from the synthetic community, particularly due to their relevance in biological and medicinal contexts, stereoselective synthetic approaches to more densely substituted derivatives remain scarce. The in-depth study presented herein, showcasing a straightforward method for the stereocontrolled synthesis of γ-lactones and γ-lactams, builds on and considerably expands the stereodivergent synthesis of 1,4-dicarbonyl compounds by a ynamide/vinyl sulfoxide coupling. A full mechanistic and computational study of the rearrangement was conducted, uncovering the role of all of the reaction components and providing a rationale for stereoselection. The broad applicability of the developed tools to streamlining synthesis is demonstrated by concise enantioselective total syntheses of (+)-nephrosteranic acid, (+)-rocellaric acid, and (+)-nephromopsinic acid.

Photochemical Synthesis of Lactones, Cyclopropanes and ATRA Products: Revealing the Role of Sodium Ascorbate.

Light-mediated processes have received significant attention, since they have re-surfaced unconventional reactivity platforms, complementary to conventional polar chemistry. γ-Lactones and cyclopropanes are prevalent moieties, found in numerous natural products and pharmaceuticals. Among various methods for their synthesis, light-mediated protocols are coming to the spotlight, although these are contingent upon the use of photoorgano- or metal-based catalysts. Herein, we introduce a novel photochemical activation of iodo-reagents via the use of cheap sodium ascorbate or ascorbic acid to enable their homolytic scission and addition onto double bonds. The developed protocol was applied successfully to the formal [3+2] cycloaddition for the synthesis of γ-lactones, traditional atom transfer radical addition (ATRA) reactions and the one-pot two-step conversion of alkenes to cyclopropanes. In all cases, the desired products were obtained in good to high yields, while the reaction mechanism was thoroughly investigated. Depending on the nature of the iodo-reagent, a halogen or a hydrogen-bonded complex is formed, which initiates the process.

Divergent functionalization of alkenes enabled by photoredox activation of CDFA and α-halo carboxylic acids.

Herein we present our studies on the solvent-controlled difunctionalization of alkenes utilizing chlorodifluoroacetic acid (CDFA) and α-halo carboxylic acids for the synthesis of γ-lactones, γ-lactams and α,α-difluoroesters. Mechanistic insights revealed that photocatalytic reductive mesolytic cleavage of the C-X bond delivers elusive α-carboxyl alkyl radicals. In the presence of an olefin molecule, this species acts as a unique bifunctional intermediate allowing for stipulated formation of C-O, C-N and C-H bonds on Giese-type adducts via single electron transfer (SET) or hydrogen atom transfer (HAT) events. These protocols exhibit great efficiency across a broad spectrum of readily available α-halo carboxylic acids and are amenable to scalability in both batch and flow. To demonstrate the versatility of this concept, the synthesis of (±)-boivinianin A, its fluorinated analog and eupomatilone-6 natural products was successfully accomplished.

Copper-catalyzed intermolecular carboesterification of unactivated aliphatic alkenes with α-carbonyl alkyl bromides via a SET process: efficient synthesis of γ-lactones

A novel and efficient copper-catalyzed carboesterification of unactivated alkenes with α-carbonyl alkyl bromides for the synthesis of γ-lactones derivatives has been developed.

An expedient copper-catalysed asymmetric synthesis of γ-lactones and γ-lactams. Application to the synthesis of lucidulactone A.

The parent Josiphos ligand gave excellent ee values (95-99%) and good yields (60-97%) in the copper-catalysed asymmetric conjugate reduction of β-aryl α,β-unsaturated lactones and lactams with PMHS. The substrates were obtained from stereospecific copper-catalysed addition of arylboronic acids to alkynoates followed by deprotection and cyclisation. The acyclic lactam precursors also underwent reduction with good ee values (83-85%) and yields (79-95%). Application of this asymmetric reduction methodology included the synthesis of natural product lucidulactone A.

Pd-Catalyzed Dual-γ-1,1-C(sp3)–H Activation of Free Aliphatic Acids with Allyl–O Moieties

Allyl alcohols represent a unique class of coupling partners in C–H functionalization reactions. In this work, we report a simple strategy that involves dual-1,1-C(sp3)–H activation of free aliphatic acids, leading to the direct synthesis of γ-lactones that contain α,β-unsaturated groups at the γ-position. Various allyl alcohols including primary, secondary, tertiary, etc., have been used as suitable coupling partners to generate a diverse range of γ-lactones. A number of aliphatic acids including the long-chain ones have been used as substrates in the protocol. A mechanistic investigation has been carried out and suggests C–H activation to be the rate-determining step and a subsequent allylic C–H activation in the reaction. The synthesized lactones having α,β-unsaturated fragments attached are expected to be useful in the synthesis of complex molecules via further synthetic manipulation.

From Ring-Expansion to Ring-Contraction: Synthesis of γ-Lactones from Cyclobutanols and Relative Stability of Five- and Six-Membered Endoperoxides toward Organic Bases

AbstractCyclobutanols undergo ring expansion with molecular oxygen in the presence of Co(acac)2 to afford 1,2-dioxane-hemiperoxyketals. In the course of acylation, we observed that endoperoxides rearranged into γ-lactone in the presence of triethylamine. Thus, a generalization of this ring contraction through a Kornblum–DeLaMare rearrangement is here reported. Application of this transformation to monosubstituted 1,2-dioxane derivatives also led to 1,4-ketoaldehydes, in proportions depending on the nature of the substituent. These same conditions applied to five-membered dioxolane analogues led to fragmentation instead, through a retro-aldol type process. This study emphasizes the difference of stability of 1,2-dioxane and 1,2-dioxolane against organic bases, 1,2-dioxolanes having proved to be particularly reactive whereas 1,2-dioxanes showed a relative tolerance under these conditions.

Iron-Catalyzed Radical Annulation of Unsaturated Carboxylic Acids with Disulfides for the Synthesis of γ-Lactones.

An efficient aerobic iron-catalyzed annulation of unsaturated carboxylic acids with disulfides has been developed. This procedure proceeds using FeCl3 as the catalyst and KI as an iodine source under an air atmosphere, which provides practical access to a wide range of substituted γ-lactone derivatives. The disclosed method is quite simple, highly atom-economic, environmentally friendly, and tolerates a broad substrate scope.

Functionalized Cyclopropanes as Versatile Intermediates for the Diversity-Oriented Synthesis of γ-Lactones, γ-Lactams and δ-Lactams

AbstractA two-step procedure for the preparation of cyclopropanecarboxaldehyde-1,1-diester from a γ,δ-epoxyester and its synthetic versatility are described herein. The epoxide ring-opening/cyclopropanation process occurs in the presence of Mg(ClO4)2 under heating, resulting in cyclopropanemethanol-1,1-diester in 65% yield. A mild TEMPO-mediated oxidation of this substrate readily generated the corresponding aldehyde in 75% yield, which was applied in the one-pot synthesis of four cyclopropylidene-γ-lactams and three δ-lactams. In addition, vinylcyclopropanes were obtained through the Wittig reaction of the aldehyde with phosphonium salts and used as precursors for tetrahydrofurans.

Lactones in the Synthesis of Prostaglandins and Prostaglandin Analogs.

In the total stereo-controlled synthesis of natural prostaglandins (PGs) and their structural analogs, a vast class of compounds and drugs, known as the lactones, are encountered in a few key steps to build the final molecule, as: δ-lactones, γ-lactones, and 1,9-, 1,11-, and 1,15-macrolactones. After the synthesis of 1,9-PGF2α and 1,15-PGF2α lactones, many 1,15-lactones of E2, E3, F2, F3, A2, and A3 were found in the marine mollusc Tethys fimbria and the quest for understanding their biological role stimulated the research on their synthesis. Then 1,9-, 1,11-, and 1,15-PG lactones of the drugs were synthesized as an alternative to the corresponding esters, and the first part of the paper describes the methods used for their synthesis. The efficient Corey procedure for the synthesis of prostaglandins uses the key δ-lactone and γ-lactone intermediates with three or four stereocenters on the cyclopentane fragment to link the PG side chains. The paper describes the most used procedures for the synthesis of the milestone δ-Corey-lactones and γ-Corey-lactones, their improvements, and some new promising methods, such as interesting, new stereo-controlled and catalyzed enantioselective reactions, and methods based on the chemical/enzymatic resolution of the compounds in different steps of the sequences. The many uses of δ-lactones not only for the synthesis of γ-lactones, but also for obtaining 9β-halogen-PGs and halogen-substituted cyclopentane intermediates, as synthons for new 9β-PG analogs and future applications, are also discussed.

Combined Chemoenzymatic Sequence for the Synthesis of γ-Lactones

Key words chemoenzymatic catalysis - lactones - Stetter reaction - NHC catalysis

A Sequential Umpolung/Enzymatic Dynamic Kinetic Resolution Strategy for the Synthesis of γ-Lactones.

Combining biological and small-molecule catalysts under a chemoenzymatic manifold presents a series of significant advantages to the synthetic community. We report herein the successful development of a two-step/single flask synthesis of γ-lactones through the merger of Umpolung catalysis with a ketoreductase-catalyzed dynamic kinetic resolution, reduction, and cyclization. This combined approach delivers highly enantio- and diastereoenriched heterocycles and demonstrates the feasibility of integrating NHC catalysis with enzymatic processes.

Deconjugated butenolide: a versatile building block for asymmetric catalysis.

The wide abundance of γ-lactones in natural products and bioactive targets calls for suitable building blocks for their enantioselective synthesis. β,γ-Unsaturated γ-butenolides, commonly known as deconjugated butenolides, owing to their easy accessibility and highly reactive nature, have emerged as the synthon of choice during the past decade for the enantioselective synthesis of γ-lactones. Their compatibility under organocatalytic, metal-catalyzed as well as cooperative catalytic conditions has resulted in numerous enantioselective transformations involving deconjugated butenolides. These reactions not only led to enantioenriched γ-lactones, but also various other heterocycles and acyclic compounds through ring-opening and fragmentation of the parent butenolide ring. The purpose of this review is to provide a comprehensive treatise on the catalytic asymmetric reactions of deconjugated butenolides reported so far. This aspect is presented alongside the preparation and reactivity comparison of deconjugated butenolides with other competing synthons of γ-lactones. Limitations of the existing protocols and the possible scope for future development are also discussed.

Photoinduced umpolung addition of carbonyl compounds with α,β-unsaturated esters enables the polysubstituted γ-lactone formation.

We herein report the photoinduced intermolecular umpolung addition of aromatic ketones/aldehydes with α,β-unsaturated esters via ketyl radical intermediates. Following an intramolecular transesterification, a variety of γ-lactone derivatives are readily accessed. Mechanistic investigations demonstrate the significant role of Hantzsch ester, which serves both as the electron and proton donor.

Synthesis of γ-Lactones by TBAI-Promoted Intermolecular Carboesterification of Carboxylic Acids with Alkenes and Alcohols.

A novel tetrabutylammonium iodide (TBAI)-promoted three-component reaction of carboxylic acid with alkene and alcohol has been developed, which represents facile and straightforward access to polysubstituted γ-lactone skeletons in moderate-to-good yields. This methodology is distinguished by the use of a commercial catalyst and readily available starting materials, wide substrate scope, and operational simplicity. Mechanistic studies suggested that this transformation went through a radical process.

Organocatalytic Gram-Scale Synthesis and Alkylation of Heteroaryl and Electron-Rich Aryl α-Substituted γ-Lactones

The synthesis of γ-lactones α-substituted with heterocycles and electron-rich aromatic rings is described. The method, based on a sequence involving an organocatalytic addition of boronic acid to the 5-hydroxyfuran-2(5H)-one, followed by reduction and lactonization, gives access to broad range of γ-lactones on a gram scale. Among these, γ-lactones bearing a benzofuran, a benzothiophene, and an indole ring were alkylated in mild catalytic conditions to construct α-quaternary stereocenters. Interesting mild oxidation reaction, using molecular oxygen, was also highlighted during this study.

Chemodivergent and Diastereoselective Synthesis of γ-Lactones and γ-Lactams: A Heterogeneous Palladium-Catalyzed Oxidative Tandem Process.

A palladium-catalyzed oxidative tandem process of enallenols was accomplished within a homogeneous/heterogeneous catalysis manifold, setting the stage for the highly chemodivergent and diastereoselective synthesis of γ-lactones and γ-lactams under mild conditions.

Regioselective Synthesis of γ-Lactones by Iron-Catalyzed Radical Annulation of Alkenes with α-Halocarboxylic Acids and Their Derivatives.

An abundant and low toxicity iron catalyst has enabled regioselective annulation of alkenes with α-halocarboxylic acids and their derivatives. The reaction proceeds smoothly without any additional ligands, bases, and additives to afford a variety of γ-lactones in good yields. A proposed reaction pathway through radical annulation is supported by some mechanistic studies, involving radical clock and isotope labeling experiments. The present method was applied to the practical iron-powder-promoted synthesis of γ-lactones.

Radical-mediated synthesis of γ-lactones by copper-catalyzed intermolecular carboesterification of alkenes with α-carbonyl alkyl bromides and H2O

A novel copper-catalyzed intermolecular carboesterification strategy of alkenes with α-carbonyl alkyl bromides is described.

Photocatalytic Synthesis of γ-Lactones from Alkenes: High-Resolution Mass Spectrometry as a Tool To Study Photoredox Reactions

A mild photocatalytic manifold for the synthesis of γ-lactones has been developed. Utilizing Ru(bpy)3Cl2 as the photocatalyst, a cheap and reproducible synthetic protocol for γ-lactones has been introduced. Mechanistic studies revealed the successful monitoring of photocatalytic reactions and radical intermediates via high-resolution mass spectrometry.