Motifs In Natural Products Research Articles

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Pyridine and piperidine are common structural motifs in natural products and pharmaceutical compounds, underscoring the importance of their synthesis. Our group has developed chiral spiro‐bicyclic bisborane catalysts that enable the efficient and highly enantioselective reduction of pyridines to chiral piperidines. Subsequent transformations allow the conversion of the piperidine products into bioactive natural products. More details are discussed in the article by Wang et al. on pages 3088—3092. image

Formal Transformation of Benzylic Carboxylic Acids to Phenols.

Phenols play a crucial role as core structural motifs in natural products and also serve as fundamental building blocks in synthetic chemistry. Apart from the known protocols for the conversion of aryl precursors to phenols (i.e., decarboxylative oxygenation), we report here the efficient synthesis of phenols from the stable and readily available benzylic carboxylic acids under mild reaction conditions. The photocatalytic conversion of carboxylic acids to peroxides is a crucial step in this strategy, allowing the subsequent C-O bond formation via Hock rearrangement.

Enantioselective Synthesis of Cyclobutylboronates

AbstractCyclobutane derivatives are important motifs in natural products and bioactive compounds. Owing to their inherent strain, the asymmetric synthesis of cyclobutanes remains a formidable challenge. With the development of various stereospecific transformations of alkylboronic esters, chiral cyclobutylboronates are expected to serve as promising synthetic intermediates for accessing chiral cyclobutane derivatives. However, obtaining highly enantioenriched cyclobutylboronates poses a daunting task in the field of organic synthesis. In this context, we highlight recent significant advances in the synthesis of chiral cyclobutylboronates.1 Introduction2 Enantioselective Borylation of Cyclobutenes3 Enantioselective Borylation of Cyclobutanes4 Other Methods5 Conclusions

Catalytic Reductive Addition of Imine for Chiral Amine Synthesis: Recent Advances and Future Perspectives

AbstractOptically active amine represents the most important structure motif in natural products and biologically active compounds. Stereoselective reductive addition of imine with the utilization of electrophilic component offers a concise and operationally simple method for the synthesis of chiral amines. This review mainly highlights recent significant synthetic methodology developments in reductive addition of imine for chiral amine synthesis including chiral auxiliary‐mediated diastereoselective transformation, asymmetric transition metal catalysis, organocatalysis, and enzymatic catalysis. In addition, the electrophilic reagents scopes and mechanistic aspects have also been introduced in this review.

6‐Hydroxy Picolinohydrazides Promoted Cu(I)‐Catalyzed Hydroxylation Reaction in Water: Machine‐Learning Accelerated Ligands Design and Reaction Optimization

Hydroxylated (hetero)arenes are privileged motifs in natural products, materials, small‐molecule pharmaceuticals and serve as versatile intermediates in synthetic organic chemistry. Herein, we report an efficient Cu(I)/6‐hydroxy picolinohydrazide‐catalyzed hydroxylation reaction of (hetero)aryl halides (Br, Cl) in water. By establishing machine learning (ML) models, the design of ligands and optimization of reaction conditions were effectively accelerated. L32 (6‐HPA‐DMCA) demonstrated high efficiency for (hetero)aryl bromides, promoting hydroxylation reactions with a minimal catalyst loading of 0.01 mol% (100 ppm) at 80 °C to reach 10000 TON or under near‐room temperature conditions for substrates containing sensitive functional groups (3.0 mol%); L42 (6‐HPA‐DTBCA) displayed superior reaction activity for chloride substrates, enabling hydroxylation reactions at 100 °C with 2‐3 mol% catalyst loading. These represent the state of art for both lowest catalyst loading and temperature in the copper‐catalyzed hydroxylation reactions. Furthermore, this method features a sustainable and environmentally friendly solvent system, accommodates a wide range of substrates, and shows potential for developing robust and scalable synthesis processes for key pharmaceutical intermediates.

6-Hydroxy Picolinohydrazides Promoted Cu(I)-Catalyzed Hydroxylation Reaction in Water: Machine-Learning Accelerated Ligands Design and Reaction Optimization.

Hydroxylated (hetero)arenes are privileged motifs in natural products, materials, small-molecule pharmaceuticals and serve as versatile intermediates in synthetic organic chemistry. Herein, we report an efficient Cu(I)/6-hydroxy picolinohydrazide-catalyzed hydroxylation reaction of (hetero)aryl halides (Br, Cl) in water. By establishing machine learning (ML) models, the design of ligands and optimization of reaction conditions were effectively accelerated. L32 (6-HPA-DMCA) demonstrated high efficiency for (hetero)aryl bromides, promoting hydroxylation reactions with a minimal catalyst loading of 0.01 mol% (100 ppm) at 80 °C to reach 10000 TON or under near-room temperature conditions for substrates containing sensitive functional groups (3.0 mol%); L42 (6-HPA-DTBCA) displayed superior reaction activity for chloride substrates, enabling hydroxylation reactions at 100 °C with 2-3 mol% catalyst loading. These represent the state of art for both lowest catalyst loading and temperature in the copper-catalyzed hydroxylation reactions. Furthermore, this method features a sustainable and environmentally friendly solvent system, accommodates a wide range of substrates, and shows potential for developing robust and scalable synthesis processes for key pharmaceutical intermediates.

Transition‐Metal Catalyzed Enantioselective Aziridination Reaction: Recent Development in Catalysis and Future Perspectives

Chiral aziridines are important motifs in natural products and biologically significant compounds, as well as one of the most valuable and versatile building blocks for the construction of diverse chiral functionalized amines. Because of the importance of chiral aziridines, various novel transition‐metal‐based catalytic systems and synthetic strategies have been established to investigate the highly effective and enantioselective aziridination process. This review outlined the recent significant advances made in the transition‐metal catalyzed enantioselective aziridination reactions, as well as the challenges and potential of the field at the current stage.

Enantioselective Hydrofunctionalization of Cyclobutenones: Total Synthesis of gem‐Dimethylcyclobutane Natural Products

AbstractCyclobutanes with a gem‐dimethyl group are common motifs in natural products. However, strategies for constructing enantioenriched gem‐dimethyl cyclobutanes are still underdeveloped. Herein, we report an enantioselective approach to synthesize a broad group of chiral 2,3‐disubstituted cyclobutanones through sequential 1,4‐conjugate addition/trapping/cross‐coupling of readily available cyclobutenones. The intermediate 2‐bromocyclobutanone provides a valuable synthetic handle for further coupling transformations. In addition, this strategy was successfully utilized to synthesize gem‐dimethyl cyclobutane‐containing natural products, including (+)‐β‐caryophyllene, (−)‐raikovenal, (−)‐1β,9αH‐5‐linoleoyloxy‐4,5‐secocaryophyllen‐4‐one, and (−)‐rumphellanones A−C.

Enantioselective Hydrofunctionalization of Cyclobutenones: Total Synthesis of gem-Dimethylcyclobutane Natural Products.

Cyclobutanes with a gem-dimethyl group are common motifs in natural products. However, strategies for constructing enantioenriched gem-dimethyl cyclobutanes are still underdeveloped. Herein, we report an enantioselective approach to synthesize a broad group of chiral 2,3-disubstituted cyclobutanones through sequential 1,4-conjugate addition/trapping/cross-coupling of readily available cyclobutenones. The intermediate 2-bromocyclobutanone provides a valuable synthetic handle for further coupling transformations. In addition, this strategy was successfully utilized to synthesize gem-dimethyl cyclobutane-containing natural products, including (+)-β-caryophyllene, (-)-raikovenal, (-)-1β,9αH-5-linoleoyloxy-4,5-secocaryophyllen-4-one, and (-)-rumphellanones A-C.

Catalytic Asymmetric Arylations of Ketimines

AbstractArylation of ketimines is the most straightforward strategy for constructing chiral α‐tertiary amines, important structural motifs found in natural products and biologically active compounds. This comprehensive review highlights the achievements in the transition metal‐catalyzed and organocatalyzed asymmetric arylations of ketimines from the seminal report published in 2010 till November 2023. The review is divided into three chapters: (1) Arylation of diaryl ketimines, (2) Arylation of aryl‐alkyl and aryl‐acyl ketimines, and (3) Arylation of acyl‐alkyl and dialkyl ketimines. Each chapter is further divided into transition metal‐catalyzed reactions (grouped by individual metals) and organocatalyzed reactions. The covered literature includes emphasis on the advantages of the reported methodology, its scope and limitations, and the description of the transition state (where applicable).

Photoredox Catalytic Access to N,O-Acetals from Enamides by Means of Electron-Poor Perylene Bisimides.

N,O-acetals are found as structural motifs in natural products and are important synthetic precursors for N-acylimines as building blocks in organic synthesis for C-C-bond formation and amines. For the synthesis of N,O-acetals, an acid-, base- and metal-free catalytic method is reported applying N,N-di-(2,6-diisopropyl)-1,7-dicyano-perylen-3,4,9,10-tetracarboxylic acid imide and N,N-di-(2,6-diisopropyl)-1,6,7,12-tetrabromo-2,5,8,11-tetracyano-perylen-3,4,9,10-tetracarboxylic acid imide as extremely electron-deficient photocatalysts. The first perylene bisimide highly selectively photocatalyzes the formation of the N,O-acetals as products in high yields, and the second and more electron-deficient perylene bisimide allows these reactions without thiophenol as an H-atom transfer reagent. Calculated electron density maps support this. The reaction scope comprises different substituents at the nitrogen of the enamides and different alcohols as starting material. Dehydroalanines are converted to non-natural amino acids which shows the usefulness of this method for organic and medicinal chemistry.

Cascade Aryne Aminoarylation for Biaryl Phenol Synthesis.

We describe a transition metal-free approach to hindered 3-amino-2-aryl phenols through a cascade nucleophilic addition / Smiles-Truce rearrangement of a functionalized Kobayashi aryne precursor. Under anionic conditions, secondary alkyl amines add to the aryne intermediate to set up an aryl transfer from a neighboring sulfonate group. The use of a sulfonate, rather than the more typical sulfonamide, enables access to phenolic biaryl products that are important motifs in natural products and pharmaceuticals.

Diazo Quinone: An Effective Phenolic Precursor for Building C(sp2)−C(sp2) Bonds

AbstractPhenolic biaryl and styryl moieties are important structural motifs in natural products, pharmaceuticals, and functional materials. Traditional cross‐coupling often requires pre‐functional substrates and is accompanied by generation of organometallic by‐products. In recent years, diazo quinone has become a new type of high‐efficiency phenolic coupling reagent for the preparation of phenolic biaryl and styryl compounds. This is because it can be used to construct C(sp2)−C(sp2) bonds in an environment‐friendly (transition‐metal‐free) or more direct way. In this review, we focus on recent advances in the field of transition‐metal‐free cross‐coupling reactions of diazo quinones with organoboranes and transition‐metal catalyzed quinoid carbene C(sp2)−H arylation reactions.

Total Synthesis of Laurane and Guaiane Sesquiterpenoids via Oxidative Nazarov Reaction

Comprehensive SummaryAs one of the most common structural motifs in natural products, cyclopentenones usually can be fabricated by Nazarov cyclization using divinyl ketones or functionalized tertiary divinyl carbinols (TDCs) as substrates. However, straightforward method for transforming unfunctionalized TDCs to their corresponding cyclopentenones is currently lacking. Herein, we wish to report the total syntheses of four structurally distinct terpenoids, namely laurane‐type marine sesquiterpenoids isolaurene, debromoaplysin and aplysin, and guaiane sesquiterpenoid guaiadienone A, all using a novel synthetic method, named oxidative Nazarov cyclization, as the key step. This work demonstrated our robust method is suitable for synthesizing various highly substituted cyclopentenones.

5-Hydroxypyrroloindoline Affords Tryptathionine and 2,2'-bis-Indole Peptide Staples: Application to Melanotan-II.

With peptides increasingly favored as drugs, natural product motifs, namely the tryptathionine staple, found in amatoxins and phallotoxins, and the 2,2'-bis-indole found in staurosporine represent unexplored staples for unnatural peptide macrocycles. We disclose the efficient condensation of a 5-hydroxypyrroloindoline with either a cysteine-thiol or a tryptophan-indole to form a tryptathionine or 2-2'-bis-indole staple. Judicious use of protecting groups provides for chemoselective stapling using α-MSH, which provides a basis for investigating both chemoselectivity and affinity. Both classes of stapled peptides show nanomolar Ki's, with one showing a sub-nanomolar Ki value.

N-substituted pyrrole carboxylic acid derivatives from 3,4-dihydroxyketons.

Since the chemical industry is largely dependent on petrol-based feedstocks, new sources are required for a sustainable industry. Conversion of biomass to high-value compounds provides an environmentally friendly and sustainable approach, which might be a potential solution to reduce petrol-based starting materials. This also applies for N-heterocycles, which are a common structural motif in natural products, pharmaceuticals and functional polymers. The synthesis of pyrroles is a well-studied and established process. Nevertheless, most routes described are not in line with the principles of green and sustainable chemistry and employ harsh reaction conditions and harmful solvents. In this study, 3,4-dihydroxyketons are used as excellent platform chemicals for the production of N-substituted pyrrole-2-carboxylic- and pyrrole-2,5-dicarboxylic acids, as they can be prepared from glucose through the intermediate d-glucarate and converted into pyrrolic acid derivatives under mild conditions in water. The scope of this so far unknown reaction was examined using a variety of primary amines and aqueous ammonium chloride leading to pyrrolic acid derivatives with N-substituents like alkane-, alkene-, phenyl- and alcohol-groups with yields up to 20 %. The combination of both, enzymatic conversion and chemical reaction opens up new possibilities for further process development. Therefore, a continuous chemo-enzymatic system was set up by first employing an immobilized enzyme to catalyze the conversion of d-glucarate to the 3,4-dihydroxyketone, which is further converted to the pyrrolic acid derivatives by a chemical step in continuous flow.

Decarboxylative Radical Sulfilimination via Photoredox, Copper, and Brønsted Base Catalysis

AbstractSulfilimines, the aza‐variants of sulfoxides, are key structural motifs in natural products, pharmaceuticals, and agrochemicals; and sulfilimine synthesis is therefore important in organic chemistry. However, methods for radical sulfilimination remain elusive, and as a result, the structural diversity of currently available sulfilimines is limited. Herein, we report the first protocol for decarboxylative radical sulfilimination reactions between sulfenamides and N‐hydroxyphthalimide esters of primary, secondary, and tertiary alkyl carboxylic acids, which were achieved via a combination of photoredox, copper, and Brønsted base catalysis. This novel protocol provided a wide variety of sulfilimines, in addition to serving as an efficient route for the synthesis of S‐alkyl/S‐aryl homocysteine sulfilimines and S‐(4‐methylphenyl) homocysteine sulfoximine. Moreover, it could be used for late‐stage introduction of a sulfilimine group into structurally complex molecules, thereby avoiding the need to preserve labile organosulfur moieties through multistep synthetic sequences. A mechanism involving photocatalytic substrate transformation and copper‐mediated C(sp3)−S bond formation is proposed.

Decarboxylative Radical Sulfilimination via Photoredox, Copper, and Brønsted Base Catalysis.

Sulfilimines, the aza-variants of sulfoxides, are key structural motifs in natural products, pharmaceuticals, and agrochemicals; and sulfilimine synthesis is therefore important in organic chemistry. However, methods for radical sulfilimination remain elusive, and as a result, the structural diversity of currently available sulfilimines is limited. Herein, we report the first protocol for decarboxylative radical sulfilimination reactions between sulfenamides and N-hydroxyphthalimide esters of primary, secondary, and tertiary alkyl carboxylic acids, which were achieved via a combination of photoredox, copper, and Brønsted base catalysis. This novel protocol provided a wide variety of sulfilimines, in addition to serving as an efficient route for the synthesis of S-alkyl/S-aryl homocysteine sulfilimines and S-(4-methylphenyl) homocysteine sulfoximine. Moreover, it could be used for late-stage introduction of a sulfilimine group into structurally complex molecules, thereby avoiding the need to preserve labile organosulfur moieties through multistep synthetic sequences. A mechanism involving photocatalytic substrate transformation and copper-mediated C(sp3 )-S bond formation is proposed.

Hydrated [3+2] Cyclotelomerization of Butafulvenes to Create Multiple Contiguous Fully Substituted Carbon Centers.

The construction of multiple continuous fully substituted carbon centers, which serve as unique structural motif in natural products, is a challenging topic in organic synthesis. Herein, we report a hydrated [3+2] cyclotelomerization of butafulvenes to create contiguous fully substituted carbon backbone. In the presence of scandium triflate, all-carbon skeleton with spiro fused tricyclic ring can be constructed in high diastereoselectivity by utilizing butafulvene as the synthon. Mechanistic studies suggest that this atom-economic reaction probably proceeds through a synergistic process containing butafulvenes dimerization and nucleophilic attack by water. In addition, the tricyclic product can undergo a series of synthetic derivatizations, which highlights the potential applications of this strategy. The recyclability of Sc(OTf)3 has also been demonstrated to show its robust performance in this hydrated cyclotelomerization.

Hydrated [3+2] Cyclotelomerization of Butafulvenes to Create Multiple Contiguous Fully Substituted Carbon Centers

AbstractThe construction of multiple continuous fully substituted carbon centers, which serve as unique structural motif in natural products, is a challenging topic in organic synthesis. Herein, we report a hydrated [3+2] cyclotelomerization of butafulvenes to create contiguous fully substituted carbon backbone. In the presence of scandium triflate, all‐carbon skeleton with spiro fused tricyclic ring can be constructed in high diastereoselectivity by utilizing butafulvene as the synthon. Mechanistic studies suggest that this atom‐economic reaction probably proceeds through a synergistic process containing butafulvenes dimerization and nucleophilic attack by water. In addition, the tricyclic product can undergo a series of synthetic derivatizations, which highlights the potential applications of this strategy. The recyclability of Sc(OTf)3 has also been demonstrated to show its robust performance in this hydrated cyclotelomerization.