Divergent Synthesis Research Articles

Selective and Divergent Synthesis of Naphthalene- and Phenanthrene-Fused Azahelicenes by Turning Rearrangement On or Off.

The Scholl reaction has been used to synthesizea variety of polycyclic aromatic hydrocarbons, where 1,2-aryl shifts have sometimes occurred to yield unique rearrangement products. However, such 1,2-aryl shifts are often uncontrollable, and the selective and divergent synthesis with or without rearrangement is desired. Here, we achieved thecontrol of the rearrangementin the Scholl reaction of carbazoles by theN-substituents.The Scholl reaction of3,6-bis{2-(2-naphthyl)phenyl}carbazoles and 3,6-bis{2-(9-phenanthrenyl)phenyl}carbazoleswith anN-benzyl group gave multiple azahelicenes via double rearrangement, while those with anN-benzoyl group gave aza[9]helicene and quadruple [4]helicene in the former and latter cases, respectively. The reaction mechanisms on the divergent reaction pathways were investigated by DFT calculations, which well supported the experimental results.

Recent Advances in Diversity-Oriented Synthesis of N-containing Organic Molecules Through Carbodiimide-based Reactions.

Carbodiimides (R-N=C=N-R) are well-known intermediates for the preparation of a variety of N-containing compounds, including heterocycles and amide linkages. Be-cause of their high reactivity and easy availability, carbodiimides have been broadly used as building blocks in the synthesis of structurally complex and diverse heterocyclic com-pounds in multi-component reactions (MCRs). Recent advances in diversity-oriented syn-thesis with carbodiimide-based MCRs are discussed in this minireview and are classified into different sections based on the key transformation involved in the reactions, such as heteroannulation and nucleophilic addition reactions which containing metal-catalyzed re-actions, multi-component reactions, and catalyst-free reactions subsections.

Mild and Chemoselective Triethylsilane-Mediated Debenzylation for Phosphate Synthesis.

The synthetic utility of tetrabenzyl pyrophosphate for achieving chemoselective phosphorylation of phenols, as well as primary, secondary, and tertiary alcohols, is reported here. Additionally, we introduce a rapid, mild, and chemoselective debenzylation procedure, enabling access to phosphates in the presence of redox sensitive groups. Finally, stoichiometrically controlled monodebenzylation provides a versatile platform for late-stage divergent synthesis of phosphodiester and phosphoramidate chemical libraries.

Palladium-Catalyzed Stereospecific Glycosylation Enables Divergent Synthesis of N-O-Linked Glycosides.

We present a versatile palladium-catalyzed glycosylation platform that enables facile access to structurally diverse N-O-linked glycosides with constantly excellent regio- and stereoselectivities. Importantly, this approach offers a broad substrate scope, low catalyst loadings, and outstanding chemoselectivity, allowing for the selective reaction of oximes/hydroximic acids over hydroxyl groups that would otherwise pose challenges in conventional glycosylation methods. The synthetic utility of this method is further exemplified through a range of synthetic transformations and late-stage modification of bioactive molecules. Overall, our method provides an efficient toolkit for the synthesis of N-O-linked glycosides, which will facilitate their subsequent biological evaluations.

Divergent Total Syntheses of Phragmalin and Khayanolide-Type Limonoids: A Torquoselective Interrupted Nazarov Approach.

The asymmetric and divergent total syntheses of two phragmalin (moluccensins G and H) and two khayanolide-type (krishnolide F and khayseneganin F) limonoids were disclosed, which employed a torquoselective interrupted Nazarov cyclization as the key step. Taken together with a Liebeskind-Srogl coupling, a benzoin condensation, and bidirectional acyloin rearrangements, our strategy would simplify the synthetic design of both phragmalin and khayanolide-type limonoids and facilitate their modular syntheses. Moreover, the described approach also provides additional insights into the biosynthetic relationships between these two distinct skeletons.

Diversity-oriented synthesis of second generation guanidinium-rich transporters toward cell-selective penetration.

Cell-penetrating peptides (CPPs) hold significant promise for intracellular delivery of various cargo molecules such as therapeutics. However, the lack of selectivity remains a critical challenge and limits the clinical application of CPPs. Using an automated peptide synthesizer, we generated a diversity-oriented library of 256 peptidomimetics containing four modified peptoid guanidine-bearing monomers incorporated alternatively with four α-amino acids. These α-amino acids were chosen to enhance lipophilic interactions with the cell membrane (Phe, 2Nal) or to bear pH-sensitive properties (His), which could enhance cancer cell selectivity. The synthesized library exhibits selective internalization, with an average selectivity index (SI) of 1.49 for HeLa cells in comparison to non-cancerous HEK293 cells. Compounds 155 and 187, containing three His residues and either Phe or 2Nal, show high cellular uptake in HeLa cells (64.6% and 75.7%, respectively) and possess an SI of 2.7 and 2.9, respectively, at the tested dose of 5μM. Altogether, these findings highlight the use of diversity-oriented library synthesis to identify cell-permeable candidates as well as their potential for targeted cellular delivery and enhanced specificity.

Diversity-oriented synthesis of functional poly(trimethylene p-phenylene) through acetoacetate-di(bromomethyl)benzene polymerization

Diversity-oriented synthesis of functional poly(trimethylene p-phenylene) through acetoacetate-di(bromomethyl)benzene polymerization

Expeditious and environmentally benign synthesis of imidazo[4,5,1-ij]quinolines via sequential Povarov reaction/reductive cyclization.

In this contribution, a novel, simple, diastereoselective and environmentally benign two-step diversity-oriented synthesis of imidazo[4,5,1-ij]quinolines is described for the first time. The synthesis of the target compounds involves a deep eutectic solvent-mediated one-pot Povarov reaction leading to the obtention of 8-nitrotetrahydroquinolines, followed by a microwave-assisted reductive cyclocondensation employing different aromatic and aliphatic aldehydes. The target compounds were obtained in up to 70% overall yield starting from commercially available o-nitroanilines, natural phenylpropanoids (trans-anethole and trans-isoeugenol) and aromatic or aliphatic aldehydes. The eutectic solvent employed in the first step was reused in four runs without observing a drastic decrease in catalytic activity, and sodium dithionite showed to be an efficient and green reducing agent for the second step. This methodology provides significant advantages in terms of synthetic and green chemistry such as mild reaction conditions, short reaction time, energy-efficiency, simple work-up procedure, low cost, scalability and utilization of renewable substrates and a reusable solvent.

Photoredox trifluoromethylation of isocyanides to access 2-trifluoromethylated quinolines and indoles

We herein report a divergent synthesis of 2-CF3 substituted quinolines and indoles via photoredox radical trifluoromethylation of ortho-vinylphenylisocyanides.

Ligand -controlled nickel-catalyzed C–O bond cleavage of silyl enol ether for the divergent synthesis of aryl alkenes and silicon-containing product

Silyl enol ethers are easily prepared from available ketones that are widely used as α-carbon nucleophiles in organic synthesis.

Siccanin-related drimane meroterpenoids: biological activities and synthesis.

Covering: 1962 to 2023Drimane (hydro)quinones biosynthetically arise from the combination of drimane-type terpenoids with phenols or equivalents. Since the isolation of siccanin in 1962 (structure identified in 1967), over 200 natural drimane (hydro)quinones have been reported. They are widespread with remarkably diverse architectures and biological functions, which are achieved by varying either the drimane subunit, hydroquinone segment, or the fusion types of drimane and hydroquinone segment both of them. This type of natural products has drawn increasing attention in the discovery of novel pharmaceutical leads. Enormous efforts have been devoted to developing efficient and divergent synthesis approaches to facilitate the SAR study of drimane (hydro)quinones, aiming for more promising functional leads. This review is arranged mainly in terms of scaffold types of drimane (hydro)quinones and further categorized on the basis of biological functions. The mechanisms of action are also briefly discussed. Synthetic methods are categorized according to the strategies forging the Csp2-Csp3 linker between drimane segments and (hydro)quinone subunits.

Three-step click assembly using trivalent platforms bearing azido, ethynyl, and fluorosulfonyl groups.

Divergent synthesis of triazoles was achieved using newly designed platform molecules possessing azide, alkyne, and fluorosulfonyl moieties. Consecutive conjugations by the sulfur(VI) fluoride exchange and following consecutive triazole formations allowed us to prepare a wide variety of bis(triazole)s by virtue of selective transformations. One-pot triple-click assembly of easily accessible modules led to the facile synthesis of middle-molecular-weight triazoles with various functional moieties.

Stereoselective Divergent Synthesis of Chiral Pyrazolone Derivatives via Multicomponent Cascade Reactions by Isothiourea Catalysis.

Isothiourea-catalyzed multicomponent cascade reactions are challenging due to the existence of competitive side reactions between multiple reaction partners and intermediates. Herein, we report a practical and efficient protocol for the stereoselective divergent synthesis of pyrazolone-derived β-amino acid esters and β-lactams by isothiourea catalysis. Two distinct reaction pathways are identified, which are controlled by esterification or lactamization of the zwitterionic intermediate. The strategy is attractive because of the convenient one-step procedure, mild conditions, high stereoselectivity, and good functional-group tolerance.

Sugar Auxiliary Group Assisted Diversity-Oriented Enzymatic Modular Synthesis of 0-Series Ganglioside Glycans.

Due to the inaccessibility of β1-4-N-acetylgalactosaminyltransferase for the direct glycan chain elongation, the enzymatic synthesis of 0-series ganglioside with extended backbone has not been explored. In this the sialic acid was enzymatically introduced as an auxiliary group to overcome the limitation of substrate specificity of Campylobacter jejuni β1-4-N-acetylgalactosaminyltransferase (CjCgtA) to achieve the synthesis of desired extended 0-series ganglioside core structures. A bacterial α2-6-sialyltransferase from Photobacterium damselae (Pd2,6ST) exhibits unexpected acceptor substrate specificity for 0-series ganglioside core structures, providing an easy access for the synthesis of complex gangliosides bearing the sialyl N-acetylgalactosamine unit. The 0-series ganglioside core structures as the key acceptor substrates were further diversified by sequential enzymatic modular assembly to generate a collection of 31 complex 0-series ganglioside glycans after removal the sugar auxiliary group of sialic acid at appropriate stage.

Copper-Catalyzed [2,3]-Sigmatropic Rearrangement of Azide-Ynamides via Selenium Ylides.

A copper-catalyzed [2,3]-sigmatropic rearrangement of azide-ynamides via selenium ylides is disclosed, which leads to the practical and divergent synthesis of a variety of tricyclic heterocycles bearing a quaternary carbon stereocenter in generally moderate to excellent yields. Significantly, this method represents the first [2,3]-sigmatropic rearrangement of the selenium ylide based on alkynes and an unprecedented [2,3]-sigmatropic rearrangement via α-imino copper carbenes.

Divergent Synthesis of 4‐Aminotriazoles Through Click Cycloaddition and Generation of Iodonium(III) Triazoles

The divergent synthesis of 4‐amino‐1,2,3‐triazoles was accomplished through the Cu‐catalyzed cycloaddition of organic azides with alkynyliodonium(III) salts, followed by Cu‐catalyzed triazole‐amine coupling involving treatment with amines and amides. The in situ formation of 1,2,3‐triazole iodonium salts is crucial to this approach, and the utilization of a Cu‐catalyst facilitates cycloaddition and C‐N bond formation. The synthesis of 1,2,3‐triazolyliodonium(III) salts proposed in this study offers advantages, including mild reaction conditions, a broad substrate scope, and operational simplicity, while also providing efficient access to a complex and diverse range of 4‐amino‐1,2,3‐triazole derivatives.

Alkoxy Substituted Brominated closo-Dodecaborates with Functionalized Aliphatic Spacers

The utilization of dodecaborate boron clusters, [B12X12]2− (X = Cl, Br, or I), as membrane carriers has been demonstrated recently, and their activity is known to be due to their superchaotropic nature. In this work, the mono-alkylation of [B12Br11OH]2− to functionalize it with an aliphatic spacer was developed with a view to expanding the known chemical space of membrane carriers based on [B12Br12]2−. A new and improved facile route for the preparation of [B12Br11OH]2−, which is an important precursor to other [B12Br11OR]2− species, is reported. Various alkoxylated [B12Br11O(CH2)5Z]2− (Z = OH, N(CO)2C6H4, CN and N3) derivatives were prepared via a divergent synthesis based on [B12Br11O(CH2)5Br]2−. One of the newly synthesized compounds was utilized as a membrane carrier, and its impact on cell viability was examined.

Copper-Catalyzed Cycloaddition/Coupling Cascades of Azomethine Imines with Alkynes for Divergent Synthesis of (Z)-Alkenyl and Alkynyl N,N'-Bicyclic Pyrazolidinones.

Copper-catalyzed cycloaddition/coupling cascades utilizing azomethine imines and alkynes have been developed for the divergent synthesis of (Z)-alkenyl and alkynyl N,N'-bicyclic pyrazolidinones by varying the reaction conditions. The choice of inert or oxidative atmosphere plays a crucial role in determining the transformation pathways. These reactions have broad substrate scopes and mild conditions, making them potentially useful.

Temperature‐Controlled Dearomative [5+1] Spiroannulation and Formal [5+2] Cyclization of Indoles with Enynones: Divergent Synthesis of Spiro‐Indolenines and Dihydrocyclohepta[b]Indolones

AbstractWe developed a temperature‐controlled intermolecular dearomative [5+1] spiroannulation and [5+2] cyclization of indoles with enynones, smoothly delivering a variety of spiroindolenines and dihydrocyclohepta[b]indolones under 40 °C and 80 °C, respectively. A three‐step cascade reaction was also realized by using OTBS or NHBoc containing enynones in the reaction with the indole under the identical condition. And a novel valuable highly‐oriented three‐dimensional indole‐based tetracyclic scaffold was produced in high yields with excellent diastereoselectivities. Additionally, various spiroindolines and spirooxindoles were facilely produced through simple operations. This highly efficient domino‐reaction represents an emblematic method for the preparation of indole‐based polycycles through the intermolecular pathway.

Controllable Phosphine-Catalyzed Three-Component Domino Reaction of Activated Alkenes with Morita-Baylis-Hillman (MBH) Carbonates: Divergent Synthesis of Densely Functionalized Cyclopentanes and Diquinanes.

An unexpected phosphine-catalyzed controllable three-component domino reaction involving [1 + 2 + 2] annulation and [1 + 2 + 2]/[3 + 2] sequential annulation reaction of 2-arylmethylidene cyanoacetates/malononitriles with Morita-Baylis-Hillman (MBH) carbonates has been developed. A broad range of densely functionalized cyclopentanes and diquinanes bearing five or four consecutive stereogenic centers, including two all-carbon quaternary stereocenters, were smoothly acquired in moderate to excellent yields under mild reaction conditions from readily available materials. Moreover, this divergent transformation enables the simultaneous generation of three or four new C-C bonds and one or two carbocyclic rings in only one step.