Synthesis of Medium-Sized Heterocycles by Transition-Metal-Catalyzed Intramolecular Cyclization.

Medium-sized heterocycles (with 8 to 11 atoms) constitute important structural components of several biologically active natural compounds and represent promising scaffolds in medicinal chemistry. However, they are under-represented in the screening of chemical libraries as a consequence of being difficult to access. In particular, methods involving intramolecular bond formation are challenging due to unfavorable enthalpic and entropic factors, such as transannular interactions and conformational constraints. The present review focuses on the synthesis of medium-sized heterocycles by transition-metal-catalyzed intramolecular cyclization, which despite its drawbacks remains a straightforward and attractive synthesis strategy. The obtained heterocycles differ in their nature, number of heteroatoms, and ring size. The methods are classified according to the metal used (palladium, copper, gold, silver), then subdivided according to the type of bond formed, namely carbon-carbon or carbon-heteroatom.

Gold(I)-Catalyzed Domino Reaction for Furopyrans Synthesis.

We report herein an efficient synthesis of furopyran derivatives through a gold(I)-catalyzed domino reaction. The cascade reaction starts with two regioselective cyclizations, a 5-endo-dig and a 8-endo-dig, followed with a Grob-type fragmentation and a hetero Diels-Alder. The obtained furopyran derivatives contain fused and spiro-heterocycles. During this one-pot process, four bonds and four controlled stereogenic centers including a quaternary center are formed.

Synthesis of Aromatic Rings Embedded in Polycyclic Scaffolds by Triyne Cycloaddition: Competition between Carbonylative and Non-Carbonylative Pathways.

Cycloadditions have emerged as some of the most useful reactions for the formation of polycyclic compounds. The carbonylative cycloaddition of triynes can lead to carbonylative and non-carbonylative competitive pathways, each leading to the formation of an aromatic ring. We report herein the one-pot synthesis of fully- and unsymmetrically-substituted tetracyclic 6,5,7,5-troponic and 6,5,6,5-benzenoid scaffolds using pre-organized triynes showing the competition between these two pathways.

Synthesis of Cyclooctatetraenes through a Palladium-Catalyzed Cascade Reaction.

Reported is a cascade reaction leading to fully substituted cyclooctatetraenes. This unexpected transformation likely proceeds through a unique 8π electrocyclization reaction of a ene triyne. DFT computations provide the mechanistic basis of this surprizing reaction.

The IMS Library: from IN-Stock to Virtual.

A chemical library is a key element in the early stages of pharmaceutical research. Its design encompasses various factors, such as diversity, size, ease of synthesis, aimed at increasing the likelihood of success in drug discovery. This article explores the collaborative efforts of computational and synthetic chemists in tailoring chemical libraries for cost-effective and resource-efficient use, particularly in the context of academic research projects. It proposes chemoinformatics methodologies that address two pivotal questions: first, crafting a diverse panel of under 1000 compounds from an existing pool through synthetic efforts, leveraging the expertise of organic chemists; and second, expanding pharmacophoric diversity within this panel by creating a highly accessible virtual chemical library. Chemoinformatics tools were developed to analyse initial panel of about 10,000 compounds into two tailored libraries: eIMS and vIMS. The eIMS Library comprises 578 diverse in-stock compounds ready for screening. Its virtual counterpart, vIMS, features novel compounds guided by chemists, ensuring synthetic accessibility. vIMS offers a broader array of binding motifs and improved drug-like characteristics achieved through the addition of diverse functional groups to eIMS scaffolds followed by filtering of reactive or unusual structures. The uniqueness of vIMS is emphasized through a comparison with commercial suppliers' virtual chemical space.

Fenestranes in synthesis: unique and highly inspiring scaffolds.

The scaffold of fenestranes is quite unique, as it contains four condensed cycles and a distorted tetracoordinated central carbon atom with bond angles greater than the regular 109°28". In this Minireview, a detailed overview on the developments regarding this compound class, including their synthesis, is given for the time period since 2006. In the past years, natural products that belong to the class of heterofenestranes have been isolated and their syntheses will also be discussed.

Two-Photon Sensitive Coumarinyl Photoremovable Protecting Groups with Rigid Electron-Rich Cycles Obtained by Domino Reactions Initiated by a 5-exo-Dig Cyclocarbopalladation.

We herein report the design, synthesis, and photophysical characterization of extended and rigid coumarinyl derivatives showing large two-photon sensitivities (δaΦu ≤ 125 GM) at 740 and 800 nm. To efficiently synthesize these complex photoremovable protecting groups (PPGs), we used step-economic domino reactions. Moreover, those new coumarinyl PPGs display unique bathochromic shifts (≤100 nm) of the uncaging subproducts as a result of the formation of a more conjugated fulvene moiety.

Synthesis of exotic polycycles such as cyclooctatrienes and fenestrenes with differential pro-apoptotic activities on human TRAIL-resistant metastatic cell lines.

New cyclooctatrienes were prepared by semihydrogenation of trienynes followed by 8π electrocyclization. Cyclooctatrienes and original fenestrenes previously reported were tested for their pro-apoptotic activities on two human cancer cell lines (THP-1 and SW620). Among the 20 new compounds tested, two compounds presented specific activities on the colon carcinomas TRAIL-resistant metastatic cell SW620, but a minor action on the monocytic leukemia THP-1 cell line. Six other compounds showed cell type specific activities: four induced apoptosis only in THP-1 cells and two only in SW620. Such differential pro-apoptotic activities suggest that these molecules could serve as potent pharmacological tools to study TRAIL associated cellular mechanisms.

Solvent Effect in Gold(I)-Catalyzed Domino Reaction: Access to Furopyrans.

We report an efficient synthesis of furopyrans through a gold(I)-catalyzed domino reaction. By starting from the same source and changing the solvent of the reaction, two classes of furopyrans are accessible. During this one-step process, which takes place in DMF, two bonds and two heterocycles are formed. DFT calculations furnish the mechanistic understanding of this transformation. The sequence includes a 5-endo-dig cyclization, a regioselective 8-endo-dig cyclization, and a retro 8π and a 6π electrocyclization.

Understanding the torquoselectivity in 8pi-electrocyclic cascade reactions: synthesis of fenestradienes versus cyclooctatrienes.

Unusual and novel polycyclic cyclooctatrienes, fenestradienes, and fenestrenes form readily from trienynes depending on the structure of the starting trienynes and the reaction conditions. The experimentally observed high torquoselectivities and complete diastereoselectivities of the 8pi-electrocyclization products have been thoroughly studied using density functional computations at B3PW91/6-31G(d,p). The different P- and M-helical topologies for the Mobius aromatic transition structures are the origin of the observed torquoselectivities in the cyclooctatrienes. The P-helical topologies direct the newly formed single bonds into a favorable equatorial position of the neighboring cycloalkane moieties (X = ring size) that retain their most stable conformation. The M-helical transition structures lead to an axial connection for the smaller rings (X = 4-6) and an equatorial connection for the seven- and eight-membered cycloalkanes. This leads to unfavorable conformations for the larger cycloalkane moieties. Experiments and computations show that for trienynes involving small neighboring cycloalkane groups (X = 4-6) M-helical topology is preferred toward cyclooctatrienes and in the following the corresponding fenestradienes can be formed as kinetic or even thermodynamic products; they convert to their more stable cyclooctatriene valence isomers derived from P-helical transition structures at higher temperatures. For larger cycloalkane moieties with more conformational flexibility only cyclooctatrienes with torquoselectivities derived from P-helical transition structures form.

Gold(I)-Catalyzed Synthesis of Furopyrans: Insight into Hetero-Diels-Alder Reactions.

We report herein the synthesis of complex molecules containing furopyran cores through a gold(I)-catalyzed hetero-Diels-Alder cascade reaction. During this process, the diene and the dienophile are produced concomitantly by the action of a single catalyst from a single starting material. Moreover, six bonds, four heterocycles, and four controlled stereogenic centers are formed in a one-step operation. DFT calculations provide the mechanistic basis of this unprecedented reaction.

Synthesis of [4.6.4.6]fenestradienes and [4.6.4.6]fenestrenes based on an 8pi-6pi-cyclization-oxidation cascade.

Fenestranes are regarded as a particularly challenging synthetic targets, and only few syntheses have been reported in the recent past. These rare compounds of synthetic and theoretical interest are a class of tetracyclic skeletons, defined as doubly a,a'-bridged spiroalkanes. The reported results are focused on the synthesis of new and original [4.6.4.6]fenestradienes 3a-f and [4.6.4.6]fenestrenes 4a-e. Our approach implies the formation of this tetracyclic structure by a reaction cascade, based on consecutive transformations starting from the trienyne 1a-f: an initial soft hydrogenation using a P-2 Nickel catalyst at room temperature, followed by a conrotatory 8p electrocyclization and a disrotatory 6p electrocyclization and a final oxidation. Several examples of this type of new compounds are described in this Communication.

A new pd-catalyzed cascade reaction for the synthesis of strained aromatic polycycles.

Two new palladium catalyzed cascade reactions involving a 4-exo-dig cyclocarbopalladation are described. These processes are shown to convert bromoenediynes and bromodienynes into strained aromatic compounds in a single step.

Synthesis of Polyheterocyclic Tropones by [2 + 2 + 2 + 1] Carbonylative Cycloaddition of Triynes.

A direct synthesis of tropones (2,4,6-cycloheptatrienes) from simple preorganized triynes has been elaborated. This simple rhodium-catalyzed domino strategy allows one-pot access to fully substituted tropones in a 6-6-7-5 tetracyclic core in average to high yields.

Synthetic applications of alpha-fluoroalkylated enones. 1. Use as dienophiles in Diels-Alder cycloadditions.

Beta-fluoroalkylated enones are efficient dienophiles in Diels-Alder cycloadditions to prepare various fluorinated cylic compounds. However, the presence of the fluoroalkyl moiety modifies the reactivity and the selectivity of these cycloadditions.

Generation and use of an equivalent of difluoroacetamide or difluoroacetate anions.

Ethers of trifluoroacetaldehyde hemiaminals can undergo dehydrofluorination under basic conditions to provide ethers of difluoroketene hemiaminals. The latter behave as equivalents of difluoroacetamide or difluoroacetate anions towards various electrophiles, yielding a range of difluoromethylcarbonyl products.