Total Synthesis Research Articles

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.

Advances in the Synthesis of 3‐Acyl‐2‐Pyridones: Strategies and Methods for Accessing the Versatile Scaffold

ABSTRACTThe syntheses and bioevaluation of 3‐acyl‐2‐pyridones have garnered significant interest in recent years as a novel class of compounds with diverse biological activities. The bioactivities cover a wide range of therapeutic areas including antimicrobial, antitumor, anti‐inflammatory, antifungal, antibiotic, neuritogenic, cytotoxic, and antiviral activities. Therefore, 3‐acyl‐2‐pyridone scaffold offers a versatile platform for the development of new molecules with potential applications in medicinal chemistry. The recent exploration on synthesis and bioevaluation of 3‐acyl‐2‐pyridones has yielded promising results, making them attractive targets for further optimization and development of new therapeutic agents. This review summarizes the available information on total synthesis of 3‐acyl‐2‐pyridone containing natural products, and the other synthetic strategies developed for accessing the 3‐acyl pyridones such as multicomponent synthesis, condensation reaction, microwave‐assisted synthesis, catalytic hydrogenation reactions, metalation reaction, Michael addition, and formylation reactions. The presented information may serve as a valuable resource for researchers working in the field of medicinal chemistry and drug discovery, stimulating further exploration and development of this intriguing scaffold.

Total Synthesis of (–)-Euphordraculoate A and (+)-Pedrolide

Total Synthesis of (–)-Euphordraculoate A and (+)-Pedrolide

Total Synthesis of (−)-Cyathin B2

Total Synthesis of (−)-Cyathin B2

Total Synthesis of (–)-Codeine via Cascade Double Heck Cyclization

Total Synthesis of (–)-Codeine via Cascade Double Heck Cyclization

Total Synthesis and Anticancer Evaluation of BZR-cotoxin IV

Anticancer peptides (ACPs) is a potential alternative for future cancer therapy. ACPs specifically inhibit cancer cells through a non-enzymatic membranolysis mechanism. One potential anticancer peptide worthy of investigation is BZR-cotoxin IV. Currently, research on BZR-cotoxin IV is limited to isolation, making it an interesting area for further development. One approach to developing BZR-cotoxin IV is through chemical synthesis techniques. This compound belongs to the group of cyclodepsipeptides that are naturally produced by the fungus Bipolaris zeicola Race 3. The synthesis of BZR cotoxin IV involves 3 steps: (1) Synthesis of the hydroxy acid precursor by conversion of L-valine amino acid to (2R)-hydroxyisovaleric acid, (2) synthesis of the linear depsipeptide using solid-phase peptide synthesis on 2-chlorotrityl chloride resin and (3) cyclization of the linear depsipeptide using solution phase synthesis to produce the BZR cotoxin IV compound with a purity of 11.7 %. BZR-cotoxin IV was characterized using HR-TOF-MS and 1H and 13C-NMR to validate the desired product. Anticancer activity testing was performed using the Resazurin assay on the HeLa cancer cell line, resulting in an IC50 of 187.50 μg/mL (214.014 μM) categorized as moderate. HIGHLIGHTS The chemical synthesis of BZR-cotoxin IV compounds has not been firstly reported. The synthesis of BZR-cotoxin IV was accomplished through a combination of solid-phase and solution-phase peptide synthesis. The objective was to synthesize and evaluate BZR-cotoxin IV for its cancer properties. GRAPHICAL ABSTRACT

Tandem Acylation and Aromatization of Vinylogous Esters: A Regiospecific Approach to Resorcinyl Ketones.

This study demonstrates the direct conversion of vinylogous esters into selectively protected 6-acyl resorcinols (4-alkoxy/aryloxy-2-hydroxy arylketones) in a regiospecific manner. Resorcinyl ketones are first-time synthesized, diverging from their traditional roots, originating from non-benzenoid pool materials. Converting cyclohexenones into phenol- or resorcinol-based arylketones remains challenging due to the stability and reactivity issues of intermediate products. Addressing this critical gap, we introduce a novel strategy: sequential one-pot acylation and oxidative aromatization of vinylogous esters. This innovative approach aims to surmount the long-standing barrier, facilitating the synthesis of diverse resorcinyl ketones. Furthermore, this method proves valuable for the synthesis of functionalized diaryl ethers and in the total synthesis of bioactive natural products and drug molecules such as angolensin, isoliquiritigenin, demethylsorbicillin, ponganone VII, and ipriflavone. It is also useful for modifying bioactive acids and alcohols by introducing a resorcinol functionality in the late stage of synthesis. Synthetic analogues of oxybenzone demonstrated superior ultraviolet (UV) absorption properties, effectively covering the entire UV-A and UV-B regions, spanning from 230 to 410 nm.

Frontispiz: Discovery, Total Synthesis, and Anti‐Inflammatory Evaluation of Naturally Occurring Naphthopyrone‐Macrolide Hybrids as Potent NLRP3 Inflammasome Inhibitors

Frontispiz: Discovery, Total Synthesis, and Anti‐Inflammatory Evaluation of Naturally Occurring Naphthopyrone‐Macrolide Hybrids as Potent NLRP3 Inflammasome Inhibitors

Stereoselective Total Synthesis of Rhodocoranes I and J.

We report the stereoselective total synthesis of rhodocoranes I and J in 10 steps and 16.4% overall yield from (S)-limonene. The synthesis was accomplished through the convergent assembly of a highly substituted chiral cyclopentanone and a lithiated furanyl silyl ketene acetal. The requisite cyclopentanone framework was strategically constructed from the chiral pool, (S)-limonene, through a sequence of steps that included a hydroboration/oxidation, ozonolysis, aldol condensation, reduction, and palladium-catalyzed diastereoselective allylic transposition. This study provides a general approach to the synthesis of the rhodocorane family, known for their antibacterial, antifungal, and cytotoxic properties.

Total Synthesis of the Humulene‐Derived Sesquiterpenoid (‐)‐Integrifolian‐1,5‐dione

AbstractThe oxygenated sesquiterpenoid (‐)‐integrifolian‐1,5‐dione, which originates from a plant that finds widespread use in South American traditional medicine, is distinguished by a rigid bicyclic framework consisting of a cyclopropane that is cis‐annulated to a cyclodecane ring. The first total synthesis of this demanding target is described, which relies on a highly selective cyclopropanation reaction of an α‐stannylated‐α‐diazoester catalyzed by a heteroleptic dirhodium paddlewheel complex, followed by an unprecedented Stille‐type cross coupling of the resulting stannylated cyclopropane with methyl iodide as the electrophilic partner to form the all‐carbon quaternary stereocenter at one of the bridgehead positions. Equally decisive was the bicyclization strategy based on lactonization/ring expansion that ultimately allowed the strained ten‐membered carbocycle to be forged.

Total Synthesis of (+)-Brevianamides A and B.

(+)-Brevianamides A (1a) and B (1b) are distinguished by their unique bicyclo[2.2.2]diazaoctane structure and have captured the interest of synthetic chemists due to their fascinating array of biological activities. The biosynthetic proposal of these classes of alkaloids led to the discovery of a number of interesting strategies. We present a biomimetic synthesis of these alkaloids starting from naturally occurring 4-hydroxy-l-proline and L-tryptophan. Gratifyingly, we emulate an alternative biosynthetic process through a unique elimination-isomerization sequence triggered by a dual-base system to generate the key aza-diene required for the Diels-Alder reaction to craft the bicyclo[2.2.2]diazaoctane structure.

Generalizing a Ligation Site at the N-Glycosylation Sequon for Chemical Synthesis of N-Linked Glycopeptides and Glycoproteins.

Chemical synthesis can generate homogeneous glycoproteins with well-defined and modifiable glycan structures at designated sites. The precision and flexibility of the chemical synthetic approach provide a solution to the heterogeneity problem of glycopeptides/glycoproteins obtained through biological approaches. In this study, we reported that the conserved N-glycosylation sequon (Asn-Xaa-Ser/Thr) of glycoproteins can serve as a general site for performing Ser/Thr ligation to achieve N-linked glycoprotein synthesis. We developed an N + 2 strategy to prepare the corresponding glycopeptide salicylaldehyde esters for Ser/Thr ligation and demonstrated that Ser/Thr ligation at the sequon was not affected by the steric hindrance brought about by the large-sized glycan structures. The effectiveness of this strategy was showcased by the total synthesis of the glycosylated receptor-binding domain (RBD) of the SARS-CoV-2 spike protein.

Total Syntheses of β- and γ-Naphthocyclinones.

After half a century from their isolation in 1974, we report the first total syntheses of β- and γ-naphthocyclinones, two dimeric pyranonaphthoquinones featuring an unusual bicyclo[3.2.1]-octadienone core. The syntheses were achieved with full stereochemical control and functional group management, relying on 1) enantioselective construction of the bicyclic core by Rh-catalyzed enantioselective 1,4-addition followed by thiolate-mediated reductive cyclization, and 2) judicious design of a common chiral, non-racemic monomer unit that is capable of divergence into the donor and acceptor units, and reunion to construct the bicyclo[3.2.1]octadienone core.

Total Synthesis of (−)-Bipolarolide D

Total Synthesis of (−)-Bipolarolide D

Total Synthesis of (±)-Anigorootin.

An 11-step synthesis of the octacyclic-fused dimeric phenylphenalenone anigorootin (phytoalexin in banana plants) is reported. The synthetic strategy uses an electrochemical dimerization as the key step, which stereospecifically installs the four asymmetric centers. Mechanistic aspects of the dimerization process are discussed.

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.

Total Synthesis of (±)-Baphicacanthcusine A Enabled by Sequential Ring Contractions.

Reported herein is the first total synthesis of the poly-pseudoindoxyl natural product baphicacanthcusine A. The synthesis leverages the oxidative rearrangement of indoles to pseudoindoxyls to install vicinal pseudoindoxyl heterocycles in a diastereoselective manner. Key steps include an acid-mediated cyclization/indole transposition, two diastereoselective oxidative ring contractions, and a site-selective C-H oxygenation. The synthesis of the oxidation precursors was guided by recognition of an element of hidden symmetry. This work provides a foundation for the chemical synthesis of other poly-pseudoindoxyl alkaloids.

Dyotropic Rearrangement of β‐Lactams: Reaction Development, Mechanistic Study, and Application to the Total Syntheses of Tricyclic Marine Alkaloids

An unprecedented dyotropic rearrangement of β‐lactams has been developed, which provides an enabling tool for the synthesis of structurally diverse γ‐butyrolactams. Unlike the well‐established dyotropic rearrangements of β‐lactones, the present reaction probably proceeds through a dual‐activation mode, and thus displays unusual reactivity and chemoselectivity. The combined computational and experimental results suggest that the dyotropic rearrangement of β‐lactams may proceed through different mechanisms depending on the nature of migrating groups (H, alkyl, or aryl). Hinging on a chemoselective H‐migration dyotropic rearrangement of β‐lactams, we have completed the divergent synthesis of tricyclic marine alkaloids (–)‐lepadiformine A, (+)‐cylindricine C, and (–)‐fasicularin within 11‐12 longest linear steps.

Dyotropic Rearrangement of β-Lactams: Reaction Development, Mechanistic Study, and Application to the Total Syntheses of Tricyclic Marine Alkaloids.

An unprecedented dyotropic rearrangement of β-lactams has been developed, which provides an enabling tool for the synthesis of structurally diverse γ-butyrolactams. Unlike the well-established dyotropic rearrangements of β-lactones, the present reaction probably proceeds through a dual-activation mode, and thus displays unusual reactivity and chemoselectivity. The combined computational and experimental results suggest that the dyotropic rearrangement of β-lactams may proceed through different mechanisms depending on the nature of migrating groups (H, alkyl, or aryl). Hinging on a chemoselective H-migration dyotropic rearrangement of β-lactams, we have completed the divergent synthesis of tricyclic marine alkaloids (-)-lepadiformine A, (+)-cylindricine C, and (-)-fasicularin within 11-12 longest linear steps.

Metal and Photocatalyst-Free Amide Synthesis via Decarbonylative Condensation of Alkynes and Photoexcited Nitroarenes.

Depending on the intrinsic photoactivity of nitroarenes, we herein developed a practical Brønsted acid-catalyzed decarbonylative amide synthesis from alkynes and photoexcited nitroarenes without any metal or photocatalyst. This method exhibited compatibility with water and air, broad substrate applicability, marvelous functional group tolerance, and wide applications in scale-up synthesis, late-stage functionalization, and total synthesis. Mechanism studies and DFT calculations supported that a 1,3,2-dioxazole intermediate was involved, and gaseous carbon monoxide was the only byproduct during amide construction.