Enantioselective Total Syntheses of Preussomerins: Control of Spiroacetal Stereogenicity by Photochemical Reaction of a Naphthoquinone through 1,6-Hydrogen Atom Transfer.

We report the enantioselective total syntheses of preussomerins EG1 , EG2 , and EG3 . The key transformation is a stereospecific photochemical reaction involving 1,6-hydrogen atom transfer to achieve retentive replacement of a C-H with a C-O bond, enabling otherwise-difficult control of the spiroacetal stereogenic center.

De novo synthesis of dimerization-ready flavan unit via intramolecular Pummerer/Friedel-Crafts cascade.

We describe the de novo synthesis of a dimerization-ready flavan derivative via the Pummerer/Friedel-Crafts cascade. This method allowed facile access to oligomeric proanthocyanidin natural products. The total synthesis of procyanidin B4 was achieved by this strategy.

Total Synthesis of Parameritannin†A2, a Branched Epicatechin Tetramer with Two Double Linkages.

The first total synthesis of parameritannin A2 (1), a branched epicatechin (EC) tetramer is reported. The "phloroglucinol trick" was used to circumvent two synthetic issues encountered when assembling four EC units, namely, the steric constraint and the formation of the C4-C6 interflavan linkage. As a substructure of the middle EC unit, phloroglucinol enabled the single-step assembly of two EC units (top and side) through A-type linkages. The middle EC unit was constructed by conducting a newly developed three-carbon flavan annulation via a Pummerer/Friedel-Crafts cascade reaction to furnish a trimeric intermediate bearing a thio-leaving group at C4 position, which allowed the final installation of the bottom EC unit.

Intramolecular Benzyne-Phenolate [4+2] Cycloadditions.

An intramolecular benzyne-phenolate [4+2] cycloaddition is reported. Benzyne precursors, having vicinal halogen-sulfonate functionalities, linked with a phenol(ate) by various tether groups undergo efficient intramolecular [4+2] cycloaddition by treatment with either Ph3 MgLi or nBuLi for halogen-metal exchange to form various benzobarrelenes.

Syntheses of doubly linked proanthocyanidins using free flavan units as nucleophiles: insight into the origin of the high regioselectivity of annulation.

A synthesis method of doubly linked flavan dimers is reported via the acid-promoted annulation reaction using nascent catechins, (+)-catechin or (-)-epicatechin, as a dianionic partner and an ethylenedioxy-bridged flavan as a dicationic partner. Procyanidins A1 and A2 were synthesized. On the high regioselectivity of the annulation reactions, model experiments and computational studies were carried out.

Stereochemical Dichotomy in Two Competing Cascade Processes: Total Syntheses of Both Enantiomers of Spiroxin†A.

The first total synthesis of the marine antibiotic spiroxin A has been achieved for both enantiomeric forms. The discovery of two competing cascade processes triggered by two orthogonal stimuli, photo-irradiation or acid/base treatment, enabled the divergent conversion of a single chiral, nonracemic bis-quinone into both enantiomers of an advanced intermediate en route to both (-)- and (+)-spiroxin A. The mechanism of the enantiodivergence is discussed.

Total Synthesis of Actinorhodin.

The enantioselective total synthesis of actinorhodin (1) is described. The synthesis features 1) dual benzyne reactions en route to the monomer, 2) the trans-selective installation of the side chain, and 3) a regioselective oxidative dimerization.

Total Synthesis of Carthamin, a Traditional Natural Red Pigment.

The first total synthesis of carthamin (3), a historic natural red pigment, has been achieved. The molecular structure was efficiently constructed by assembling two equivalents of the in situ generated lithiated monomers and triisopropyl orthoformate. This synthesis confirms the structure proposed in 1996.

Intramolecular photoredox reactions of 1,2-naphthoquinone derivatives.

Photoirraditation of substituted 1,2-naphthoquinones gives the corresponding oxacycle via intramolecular redox reaction, which enabled net CH functionalization of the proximal position to the excited carbonyl group of the quinones. The substrate scope and mechanistic insights are described.

Impact of Green Tea Catechin ECG and Its Synthesized Fluorinated Analogue on Prostate Cancer Cells and Stimulated Immunocompetent Cells.

Among the known or suspected risk factors, inflammation plays an important role in infectious and non-infectious pathways leading to cancer. Green tea polyphenols have been associated with reducing inflammation and protection against carcinogenesis, especially in prostate cancer. While most of the research in this field, so far, has focussed on epigallocatechin-3-O-gallate only, we studied epicatechin-3-O-gallate, the second most abundant green tea polyphenol with essential therapeutic potential, to obtain a more detailed understanding of its anti-tumor and anti-inflammatory action. Furthermore, to improve the bioactivity of (-)-epicatechin-3-O-gallate, we synthesized a difluoro analogue, called (-)-5,7-difluoro-epicatechin-3-O-gallate. Both compounds reduced cell proliferation of human primary inflammatory lymphocytes in an apoptosis-specific fashion, while (-)-5,7-difluoro-epicatechin-3-O-gallate had a significantly higher activity compared to the natural product (-)-epicatechin-3-O-gallate. Treatment of low-metastatic LNCaP and high-metastatic PC-3 prostate cancer cells with (-)-epicatechin-3-O-gallate and (-)-5,7-difluoro-epicatechin-3-O-gallate demonstrated a dose-dependent inhibition of cell viability in the low micromolar range. These effects suggest that (-)-epicatechin-3-O-gallate and the more effective (-)-5,7-difluoro-epicatechin-3-O-gallate could be therapeutically used to inhibit tumorigenesis during initiation, promotion, and progression by diminishing the amount of inflammation due to a reduction of inflammatory lymphocytes. Further studies are needed to prove this in in vivo experiments.

Synthesis of Oxygenated ortho-Methylbenzaldehydes via Aryne [2+2] Cycloaddition and Benzocyclobutenol Ring Opening.

Herein, a two-step procedure for the preparation of oxygenated ortho-methylbenzaldehyde derivatives, starting from commercially available bromoarenes, is described. The synthesis features the simultaneous and highly regioselective installation of both the methyl and the formyl group onto the benzene core via benzyne [2+2] cycloadditions with acetaldehyde lithium enolate to give the corresponding benzocyclobutenols in high yields. Bond-selective ring opening of the benzocyclobutenols under basic conditions in methanol delivers the title compounds.

Stereocontrolled Total Syntheses of (-)-Rotenone and (-)-Dalpanol by 1,2-Rearrangement and SN Ar Oxycyclizations.

The total syntheses of (-)-rotenone and (-)-dalpanol have been achieved by a group-selective, stereospecific 1,2-shift of an epoxy alcohol and SN Ar cyclizations. Three oxacycles are constructed, thus illustrating a versatile synthetic route to various rotenoids.

Stereospecificity in Intramolecular Photoredox Reactions of Naphthoquinones: Enantioselective Total Synthesis of (-)-Spiroxin†C.

Intramolecular photoredox reactions of naphthoquinone derivatives were found to proceed in a stereospecific manner. This method was used as a basis for the enantioselective total synthesis of (-)-spiroxin C.

Toward Naphthocyclinones: Doubly Connected Octaketide Dimers with a Bicyclo[3.2.1]octadienone Core by Thiolate-Mediated Cyclization.

A viable method is reported for the synthesis of the bicyclo[3.2.1]octadienone scaffold in naturally occurring octaketide dimers. The procedure employs a reductive cyclization reaction mediated by an unusual ethanedithiol monosodium salt.

Annulation approach to doubly linked (A-type) oligocatechins: syntheses of (+)-procyanidin A2 and (+)-cinnamtannin B1.

The first stereoselective syntheses of doubly linked (A-type) oligocatechins, (+)-procyanidin A2 and (+)-cinnamtannin B1, have been achieved. Ethylenedioxy-bridged flavans served as excellent platforms, thus allowing annulation with nucleophilic catechin units in a stereoselective manner. An additional key was the new synthetic approach to selectively protected nucleophilic catechin, thus enabling regioselective construction of the key dioxabicyclo skeleton of the A-type oligocatechins.

One-Pot Synthesis of Functionalized Benzotropones via a Phthalide Ring-Opening/Intramolecular Aldol Condensation Cascade.

A one-pot protocol was developed for the synthesis of functionalized benzotropone derivatives via a nucleophilic phthalide ring opening by a 5-lithiated dioxinone derivative, followed by an intramolecular aldol condensation. The method demonstrates exceptional versatility with diverse substrates, yielding a variety of functionalized benzotropones. Subsequent transformations of the obtained benzotropone derivatives were explored for their potential applications.

Atomic-resolution structure analysis inside an adaptable porous framework.

We introduce a versatile metal-organic framework (MOF) for encapsulation and immobilization of various guests using highly ordered internal water network. The unique water-mediated entrapment mechanism is applied for structural elucidation of 14 bioactive compounds, including 3 natural product intermediates whose 3D structures are clarified. The single-crystal X-ray diffraction analysis reveals that incorporated guests are surrounded by hydrogen-bonded water networks inside the pores, which uniquely adapt to each molecule, providing clearly defined crystallographic sites. The calculations of host-solvent-guest structures show that the guests are primarily interacting with the MOF through weak dispersion forces. In contrast, the coordination and hydrogen bonds contribute less to the total stabilization energy, however, they provide highly directional point interactions, which help align the guests inside the pore.

Synthesis and determination of the absolute configuration of cavicularin by a symmetrization/asymmetrization approach.

Taking the strain: The asymmetric total synthesis and stereochemical assignment of (-)-cavicularin, which features a highly strained polycyclophane ring system, has been achieved. The key features of this synthesis are 1) macrocyclization by an SN Ar reaction, 2) group-selective reaction to induce planar chirality in a highly stereoselective manner, and 3) radical transannulation to construct the highly strained ring system.

Total Syntheses of Sparsomycin and Sparoxomycins A1 and A2 via Sulfenate-Anion-Mediated Iterative C-S Bond Formation.

The total synthesis of the pyrimidinylpropenamide antibiotics sparsomycin and sparoxomycins A1 and A2 has been achieved. The synthesis of sparsomycin relies on the iterative nucleophilic attack of sulfenate anions on alkyl halides to construct the dithioacetal monoxide chain with high diastereoselectivity. Subsequently, the reagent-controlled diastereoselective oxidation of the terminal sulfide moiety of sparsomycin directly provides sparoxomycins A1 and A2.

Unified approach to catechin hetero-oligomers: first total synthesis of trimer EZ-EG-CA isolated from Ziziphus jujuba.

A catechin hetero-trimer isolated from Ziziphus jujuba has been synthesized. Among three constituent monomers, (-)-epiafzelechin and (-)-epigallocatechin were prepared by de novo synthesis. Trimer formation relied on the unified approach to oligomers based on the bromo-capping and the orthogonal activation, reaching the reported structure of the natural product.