Concise Total Synthesis Research Articles

Synthesis and Biological Activity of Tetracyclic Dispiro Core Derivatives of Natural Products Dispirocochlearoids A-C.

Natural products dispirocochlearoids A-C, which are meroterpenoids derived from Ganoderma fungi, feature a 6/6/5/6/6/6 ring system and exhibit selective COX-2 inhibitory activity. Herein, the concise total synthesis of the tetracyclic core structure of dispirocochlearoids A-C was achieved through an aldol reaction/cyclization/deprotection/cyclization cascade sequence. A series of simplified tetracyclic analogues was successfully constructed and their anti-inflammatory activity was further explored, with several tetracyclic analogues (such as compound 8ab) exhibiting strong inhibitory activity against IL-1β expression in lipopolysaccharide-stimulated bone marrow-derived macrophage cells (IC50 = 2.8 μM).

Fe‐Catalyzed α‐C(sp3)−H Amination of N‐Heterocycles

AbstractNitrogen‐heterocycles are privileged structures in both marketed drugs and natural products. On the other hand, C−H amination reactions furnish unconventional and straightforward approaches for the construction of C−N bonds. Yet, most of the known methods rely on precious metal catalysts. Herein we report a site‐selective intermolecular C(sp3)−H amination of N‐heterocycles, catalyzed by inexpensive FeCl2, which allows the functionalization of a wide range of pharmaceutically relevant cyclic amines. The C−H amination occurs site‐selectively in α‐position to the nitrogen atom, even when weaker C−H bonds are present, and furnishes Troc‐protected aminals or amidines. The method employs the N‐heterocycle as limiting reagent and is applicable to the late‐stage functionalization of complex molecules. Its synthetic potential was further illustrated through the derivatization of α‐aminated products and the application to a concise total synthesis of the reported structure for senobtusin. Mechanistic studies allowed to propose a plausible reaction mechanism involving a turnover‐limiting Fe‐nitrene generation followed by fast H atom transfer and radical rebound.

Fe-Catalyzed α-C(sp3)-H Amination of N-Heterocycles.

Nitrogen-heterocycles are privileged structures in both marketed drugs and natural products. On the other hand, C-H amination reactions furnish unconventional and straightforward approaches for the construction of C-N bonds. Yet, most of the known methods rely on precious metal catalysts. Herein we report a site-selective intermolecular C(sp3)-H amination of N-heterocycles, catalyzed by inexpensive FeCl2, which allows the functionalization of a wide range of pharmaceutically relevant cyclic amines. The C-H amination occurs site-selectively in α-position to the nitrogen atom, even when weaker C-H bonds are present, and furnishes Troc-protected aminals or amidines. The method employs the N-heterocycle as limiting reagent and is applicable to the late-stage functionalization of complex molecules. Its synthetic potential was further illustrated through the derivatization of α-aminated products and the application to a concise total synthesis of the reported structure for senobtusin. Mechanistic studies allowed to propose a plausible reaction mechanism involving a turnover-limiting Fe-nitrene generation followed by fast H atom transfer and radical rebound.

Discovery and Total Synthesis of Anhydrotuberosin as a STING Antagonist for Treating Autoimmune Diseases

Excessive activation of the stimulator of the interferon gene (STING) pathway has been identified as a significant contributor to various autoimmune diseases, such as STING‐associated vasculopathy with infantile‐onset (SAVI) and inflammatory bowel disease (IBD). However, discovering effective STING antagonists for treating STING‐mediated autoimmune disorders remains challenging. Herein, we identified the natural product anhydrotuberosin (ATS) as a potent STING antagonist by a high‐throughput chemical screen and follow‐up biological validations. However, the limited supply from natural product isolation impeded the pharmacological evaluations of ATS. Accordingly, we developed a concise and scalable total synthesis of ATS in 6 steps. Enabled by total synthesis, we further extensively investigated ATS’s mode of action and evaluated its therapeutic potential. Remarkably, ATS inhibits STING signaling in PBMCs derived from three SAVI patients. ATS showed decent pharmacokinetic parameters and strongly alleviated tissue inflammation in DSS‐induced IBD colitis and Trex1‐/‐ autoimmune animal models with low toxicity. Collectively, this research lays the foundation for developing novel STING antagonists as an effective therapy for autoinflammatory and autoimmune diseases.

Discovery and Total Synthesis of Anhydrotuberosin as a STING Antagonist for Treating Autoimmune Diseases

Excessive activation of the stimulator of the interferon gene (STING) pathway has been identified as a significant contributor to various autoimmune diseases, such as STING‐associated vasculopathy with infantile‐onset (SAVI) and inflammatory bowel disease (IBD). However, discovering effective STING antagonists for treating STING‐mediated autoimmune disorders remains challenging. Herein, we identified the natural product anhydrotuberosin (ATS) as a potent STING antagonist by a high‐throughput chemical screen and follow‐up biological validations. However, the limited supply from natural product isolation impeded the pharmacological evaluations of ATS. Accordingly, we developed a concise and scalable total synthesis of ATS in 6 steps. Enabled by total synthesis, we further extensively investigated ATS’s mode of action and evaluated its therapeutic potential. Remarkably, ATS inhibits STING signaling in PBMCs derived from three SAVI patients. ATS showed decent pharmacokinetic parameters and strongly alleviated tissue inflammation in DSS‐induced IBD colitis and Trex1‐/‐ autoimmune animal models with low toxicity. Collectively, this research lays the foundation for developing novel STING antagonists as an effective therapy for autoinflammatory and autoimmune diseases.

A Concise Formal Total Synthesis of (±)‐Laurokamurene B and (±)‐β‐Cuparenone

AbstractThe study describes a concise four‐step formal total synthesis of racemic (±)‐laurokamurene B, a sesquiterpene with a rearranged laurene carbon framework. This method also extends to the formal total synthesis of β‐cuparenone. Compared with previously reported laurokamurene B's syntheses, our approach significantly reduces the total number of reaction steps by leveraging the known scaffolds as the key concept. Optimized esterification for the generation of appropriately substituted cinnamate esters, one‐pot polyphosphoric acid (PPA) mediated fragmentation followed by Friedel–Crafts acylation, and intramolecular cyclization led to the efficient construction of pivotal intermediate 3‐arylcyclopent‐2‐en‐1‐one with a quaternary center; subsequent α‐methylation and reductive deoxygenation resulted into the marine natural product (±)‐laurokamurene B. Additionally, β‐methylation and deoxygenation of the obtained key 3‐arylcyclopente‐2‐en‐1‐one intermediate could also serve for the formal total synthesis of (±)‐β‐cuparenone in the shortest approach.

A Concise Asymmetric Total Synthesis of (+)-8-Epigrosheimin via Catalyst-Free Tandem Allylboration–Lactonization

AbstractA concise and scalable asymmetric synthesis of (+)-8-epigrosheimin is reported in nine steps using only three column chromatographic purifications with an overall yield 47.0% from (R)-(–)-carvone. Two synthetic routes are evaluated by catalyst-free tandem allylboration–lactonization of two carvone-derived aldehydes and subsequent ene cyclization, where strategy via Lee–Lay aldehyde is found to be more effective for 8-epigrosheimin.

Concise and Modular Chemoenzymatic Total Synthesis of Bisbenzylisoquinoline Alkaloids.

The bisbenzylisoquinoline alkaloids (bisBIAs) have attracted tremendous attention from the synthetic community due to their diverse and intriguing biological activities. Herein, we report the convergent and modular chemoenzymatic syntheses of eight bisBIAs bearing various substitutes and linkages in 5-7 steps. The gram-scale synthesis of various well-designed enantiopure benzylisoquinoline monomers was accomplished through an enzymatic stereoselective Pictet-Spengler reaction, followed by regioselective enzymatic methylation or chemical functionalization in a sequential one-pot process. A modified intermolecular copper-mediated Ullmann coupling enabled the concise and efficient total synthesis of five different linear bisBIAs with either head-to-tail or tail-to-tail linkage. A biomimetic oxidative phenol dimerization selectively formed the sterically hindered, electron-rich diaryl ether bond, and subsequent intramolecular Suzuki-Miyaura domino reaction or Ullmann coupling facilitated the first enantioselective total synthesis of three macrocyclic bisBIAs, including ent-isogranjine, tetrandrine and O-methylrepandine. This study highlights the great potential of chemoenzymatic strategies in the total synthesis of diverse bisBIAs and paves the way to further explore the biological functions of these natural products.

Concise and Modular Chemoenzymatic Total Synthesis of Bisbenzylisoquinoline Alkaloids

The bisbenzylisoquinoline alkaloids (bisBIAs) have attracted tremendous attention from the synthetic community due to their diverse and intriguing biological activities. Herein, we report the convergent and modular chemoenzymatic syntheses of eight bisBIAs bearing various substitutes and linkages in 5‐7 steps. The gram‐scale synthesis of various well‐designed enantiopure benzylisoquinoline monomers was accomplished via an enzymatic stereoselective Pictet–Spengler reaction, followed by regioselective enzymatic methylation or chemical functionalizations in a sequential one‐pot process. A modified intermolecular copper‐mediated Ullmann coupling enabled the concise and efficient total synthesis of five different linear bisBIAs with either head‐to‐tail or tail‐to‐tail linkage. A biomimetic oxidative phenol dimerization selectively formed the sterically hindered, electron‐rich diaryl ether bond, and subsequent intramolecular Suzuki–Miyaura domino reaction or Ullmann coupling facilitated the first enantioselective total synthesis of three macrocyclic bisBIAs, including ent‐isogranjine, tetrandrine and O‐methylrepandine. This study highlights the great potential of chemoenzymatic strategies in the total synthesis of diverse bisBIAs and paves the way to further explore the biological functions of these natural products.

Concise Total Synthesis of (-)-Codeine.

Codeine and morphine are among the few natural products that are used directly as drugs for medical treatment. However, the availability of these is widely dependent on natural resources. Herein, we report an efficient enantioselective seven-step synthesis of (-)-codeine starting from simpler starting materials. The key steps involve microwave-assisted intramolecular cascade double heck cyclization to access the ABCE ring of opium alkaloids with the required stereocenters in one pot. A photoinduced intramolecular hydroamination of carboxamide forms the D ring and completes the pentacyclic core of the morphinans. Following that, an oxidation followed by global reduction leads to the formation of (-)-codeine. Our synthesis relies on simple and classical reactions to address the opium alkaloids and will serve as an efficient route to access the other morphinans.

Biomimetic and Concise Total Syntheses of Prenylated and Bicyclo[2.2.2]diazaoctane-Containing Indole Alkaloids Including Taichunamide A, Notoamide N and Versicolamide B.

Total syntheses of the title prenylated indole alkaloids together with seven others are reported. Biogenetic considerations have been employed in devising the reaction sequences leading to these targets with, in the opening stages, electrochemically-derived indole-3-carboxaldehyde 15 being subject to an aldol-type condensation reaction involving diketopiperazine derivative 19. This led, after prototopic shifts, intramolecular Diels-Alder cycloaddition and hydrolysis/deprotection steps, to the racemic forms of the bicyclo[2.2.2]diazaoctane-containing natural product stephacidin A (2) and its C6 epimer 3. Epoxidation of the last compound afforded, following rearrangement of the primary oxidation products, a mixture of (±)-taichunamide A [(±)-4] and (±)-versicolamide B [(±)-7]. Related protocols allowed for the conversion of (±)-stephacidin A [(±)-2] into (±)-notoamide B [(±)-5]. Analogous aldol condensation, nucleophilic reduction, and epoxidation steps led to the formation of (-)-notoamide E and its conversion into notoamide C as well as the indole fragmentation product amoenamide E. A late-stage chlorination reaction applied to (±)-stephacidin A provided access to the spirocyclic oxindole (±)-notoamide N [(±)-6].

Enantioselective Total Synthesis of (-)-Cyathin B2: A Desymmetric Double-Allylboration Approach.

A powerful Pt-catalyzed asymmetric diboration/desymmetric double-allylboration cascade reaction has been developed for the construction of synthetically useful, densely functionalized hydrindanes with five stereocenters, including three quaternary ones, in good yields and excellent enantiomeric excess (ee) values within a single synthetic operation. A unified strategy utilizing this key tandem methodology enabled the concise asymmetric total synthesis of cyathane diterpene (-)-Cyathin B2 in 14 steps from commercially available starting materials, thereby demonstrating its remarkable potential in the synthesis of hydrindane-containing natural products and pharmaceuticals.

Concise and Stereospecific Total Synthesis of Arenastatin A and Its Segment B Analogs.

A novel and concise synthetic method for arenastatin A, a cytotoxic cyclic depsipeptide of marine origin, was developed in this study. The convergent assembly of the four segments, including the cross-metathesis reaction, gave a cyclization precursor, and Fmoc deprotection caused simultaneous macrocyclization. The Corey-Chaykovsky reaction using a chiral sulfur ylide afforded arenastatin A with complete stereoselectivity in the longest linear sequence of seven reaction steps from the known compound. Using this synthetic method, some analogs of segment B were prepared through a late-stage diversification strategy. The simple SN2 reaction of the thiolate toward the tosylate precursor, prepared using almost the same synthetic method as described above, provided the desired sulfide analogs.

Asymmetric Synthesis of the Indolo[2,3‐α]quinolizine Alkaloid (+)‐Cuscutamine via a Diastereoselective Intramolecular Pictet‐Spengler Reaction

AbstractA concise total synthesis of Cuscutamine was achieved involving a diastereoselective intramolecular acyl iminium ion mediated Pictet‐Spengler reaction. This synthetic strategy provided a direct route to (11S, 13R)‐Cuscutamine (2) in only 3 steps with an overall yield of 56 % and an enantiomeric ratio of 88 %. The diastereoselectivity of the reaction is consistent with previous studies that proceed via more highly puckered transition states and the present results thus reveal the importance of the steric contributions to the observed diastereoselectivity.

Stereodivergent Total Synthesis of Tacaman Alkaloids.

This paper describes a concise, asymmetric and stereodivergent total synthesis of tacaman alkaloids. A key step in this synthesis is the biocatalytic Baeyer-Villiger oxidation of cyclohexanone, which was developed to produce seven-membered lactones and establish the required stereochemistry at the C14 position (92 % yield, 99 % ee, 500 mg scale). Cis- and trans-tetracyclic indoloquinolizidine scaffolds were rapidly synthesized through an acid-triggered, tunable acyl-Pictet-Spengler type cyclization cascade, serving as the pivotal reaction for building the alkaloid skeleton. Computational results revealed that hydrogen bonding was crucial in stabilizing intermediates and inducing different addition reactions during the acyl-Pictet-Spengler cyclization cascade. By strategically using these two reactions and the late-stage diversification of the functionalized indoloquinolizidine core, the asymmetric total syntheses of eight tacaman alkaloids were achieved. This study may potentially advance research related to the medicinal chemistry of tacaman alkaloids.

Stereodivergent Total Synthesis of Tacaman Alkaloids

AbstractThis paper describes a concise, asymmetric and stereodivergent total synthesis of tacaman alkaloids. A key step in this synthesis is the biocatalytic Baeyer–Villiger oxidation of cyclohexanone, which was developed to produce seven‐membered lactones and establish the required stereochemistry at the C14 position (92 % yield, 99 % ee, 500 mg scale). Cis‐ and trans‐tetracyclic indoloquinolizidine scaffolds were rapidly synthesized through an acid‐triggered, tunable acyl‐Pictet–Spengler type cyclization cascade, serving as the pivotal reaction for building the alkaloid skeleton. Computational results revealed that hydrogen bonding was crucial in stabilizing intermediates and inducing different addition reactions during the acyl‐Pictet–Spengler cyclization cascade. By strategically using these two reactions and the late‐stage diversification of the functionalized indoloquinolizidine core, the asymmetric total syntheses of eight tacaman alkaloids were achieved. This study may potentially advance research related to the medicinal chemistry of tacaman alkaloids.

Concise Total Syntheses of (-)-Crinipellins A and B Enabled by a Controlled Cargill Rearrangement.

Herein, we report concise total syntheses of diterpene natural products (-)-crinipellins A and B with a tetraquinane skeleton, three adjacent all-carbon quaternary centers, and multiple oxygenated and labile functional groups. Our synthesis features a convergent Kozikowski β-alkylation to unite two readily available building blocks with all the required carbon atoms, an intramolecular photochemical [2 + 2] cycloaddition to install three challenging and adjacent all-carbon quaternary centers and a 5-6-4-5 tetracyclic skeleton, and a controlled Cargill rearrangement to rearrange the 5-6-4-5 tetracyclic skeleton to the desired tetraquinane skeleton. These strategically enabling transformations allowed us to complete total syntheses of (-)-crinipellins A and B in 12 and 13 steps, respectively. The results of quantum chemical computations revealed that the Bronsted acid-catalyzed Cargill rearrangements likely involve stepwise paths to products and the AlR3-catalyzed Cargill rearrangements likely involve a concerted path with asynchronous alkyl shifting events to form the desired product.

Lewis Acid-Driven Inverse Hydride Shuttle Catalysis.

Inverse hydride shuttle catalysis provides a multicomponent platform for the highly efficient synthesis of alkaloid frameworks with exquisite diastereoselectivity. However, a number of limitations hinder this method, primarily the strict requirement for highly electron-deficient acceptors. Herein, we present a general Lewis acid-driven approach to address this constraint, and have developed two broad strategies enabling the modular synthesis of complex azabicycles that were entirely unattainable using the previous method. The enhanced synthetic flexibility facilitates a streamlined asymmetric cyclization, leading to a concise total synthesis of the alkaloid (-)-tashiromine.

Lewis Säure‐Getriebene Inverse Hydrid‐Shuttle Katalyse

AbstractInverse Hydrid‐Shuttle Katalyse bildet eine Plattform für die hocheffiziente und diastereoselektive Synthese von Alkaloidstrukturen durch Multikomponentenreaktionen. Mehrere Einschränkungen hindern jedoch die breite Anwendbarkeit dieses Ansatzes, darunter vor allem die Notwendigkeit nach besonders elektronenarmen Akzeptoren. Hier präsentieren wir einen allgemeinen, durch Lewis Säuren getriebenen Ansatz, um diese Einschränkung anzugehen, und haben zwei Strategien entwickelt, die die modulare Synthese komplexer azabicyclischer Systeme ermöglichen, die mit der früheren Methode unerreichbar waren. Die so gewonnene synthetische Flexibilität führt zu einer verbesserten asymmetrischen Cyclisierung, die eine kurze Totalsynthese des Alkaloids (−)‐Tashiromin ermöglicht hat.

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.