•One-pot synthesis of procyanidin A skeleton has been described.•3-Arylpropiolaldehydes or dibromocinnamaldehydes can be employed.•The method is efficient and simple and can be useful for the total synthesis of procyanidins.Arylpropynals and two equivalents of phloroglucinol react to produce pentacyclic ketals. In addition, 4-methoxydibromocinnamaldehyde also reacted to form procyanidin A-skeleton.Arylpropynals and two equivalents of phloroglucinol react to produce pentacyclic ketals. In addition, 4-methoxydibromocinnamaldehyde also reacted to form procyanidin A-skeleton.Download high-res image (65KB)Download full-size image

Methyl coumalate reacts with enol ethers to form stable adducts which can be converted into isophthalates in good to excellent yields. Alkyl vinyl ethers afford higher yields of isophthalates than enol silyl ethers. The adduct of the enol silyl ether of acetophenone with methyl coumalate reacted with PTSA to produce a styryl coumalate.

•Developed efficient routes for synthesis of atractylodinol analogs that inhibit PRRSV replication.•Determined the presence of a bis-enyne subunit was critical for optimal antiviral activity.•Identified six analogs of atractylodinol with IC50 of 0.4–1.4 mM in vitro.•Determined inhibition of PRRSV in MARC-145 cells occurs primarily at a post-entry step during virus replication.Porcine reproductive and respiratory syndrome virus (PRRSV) is the etiological agent of PRRS, an economically significant disease of swine worldwide. PRRSV is poorly controlled by the currently available vaccines, and alternative control strategies are needed to help prevent the continual circulation of the virus. Previously, we developed a synthetic route for the natural compound atractylodinol and demonstrated anti-PRRSV activity in vitro. However, the synthetic route was inefficient and the yield was poor. To identify PRRSV inhibitors that could be synthesized easily and cost-effectively, we synthesized a series of atractylodinol analogs and characterized their anti-PRRSV activity in vitro. A furan-substituted bis-enyne subunit was found to be critical for PRRSV inhibition. Six analogs had potent inhibitory activity against PRRSV with 50% inhibition concentration (IC50) of 0.4–1.4 μM and 50% cytotoxic concentration (CC50) of 209–1537 μM in MARC-145 cells. Three of the most promising compounds also demonstrated significant antiviral activity and low cytotoxicity in porcine macrophages. Inhibition of PRRSV in MARC-145 cells occurred primarily at a post-entry step during PRRSV replication, between 4 and 12 h post-entry. These results suggest that atractylodinol analogs are promising antiviral candidates that could augment current PRRSV control strategies.

•A synthesis of an inhibitor of the PRRS virus is described.•Analogs were evaluated for viral inhibition.•Analog 8 shows excellent inhibition of the PRRS virus.A direct synthesis of atractylodinol from 2-furylbutenyne and bromoacetylene 6 is reported. Both compounds 1 and 8 showed greater than 99% virus inhibition.

At ambient temperature, triacetic acid lactone reacts with amines to produce 4-amino-2-pyrones. If the temperature is raised to 100 °C, 4-hydroxy-2-pyridones are generated.

An improved aldol protocol for the synthesis of 6-styrenylpyrones is reported. The first synthesis of PTP1B inhibitor 1 and 4 has been described.

Wine is composed of a variety of tannins, of which a sub-class includes salidrosides, which are largely uninvestigated compounds. The first syntheses of galloylated salidrosides are reported in 7 steps from commercially available starting materials through a platform approach. The antimicrobial activity of the salidrosides against Escherichia coli strains is described.

Diverse functionalized aromatic compounds are constructed from captodative dienophiles with exclusive regioselectivity. 100% biorenewable dimethyl terephthalate (DMT) from methyl coumalate and methyl pyruvate is achieved in a one-pot, Diels–Alder/decarboxylation/elimination sequence in nearly quantitative yield. The DMT system is solvent-free and purification is accomplished through recrystallization. DMT hydrolysis reveals the co-monomer terephthalic acid (TPA) as a bio-based drop-in replacement for the polymer industry, avoiding harsh oxidation and petrochemicals.

The first successful inverse electron-demand Diels–Alder has been demonstrated with the 2-pyrone methyl coumalate in conjunction with substituted indoles. Utilizing 1-alkyl-3-chloroindoles as the electron-rich dienophile efficiently generates carbazoles without the need for additional metal catalysts. Through a thermal, one-pot Diels–Alder/decarboxylation/elimination domino sequence, access to a class of 3-methylcarbazoles is rapidly generated with exclusive regiocontrol in up to 90% yield.

The conversion of naturally-occurring malic acid to the 2-pyrone methyl coumalate was optimized using a variety of acid catalysts. Coupling methyl coumalate with electron-rich dienophiles in an inverse electron-demand Diels–Alder (IEDDA)/decarboxylation/elimination domino sequence resulted in an investigation of the scope and limitations of the methodology. The thermal, metal-free, and one-pot procedure allows regioselective access to diverse aromatic compounds including tricyclic, biphenyl, and pyridinyl systems for elaboration. A comparison with analogous pyrones demonstrates the striking efficacy of methyl coumalate as a versatile platform for the generation of biorenewable functionalized benzoates.

Substituted rosamines are efficiently prepared through a new organometallic addition to an imine-substituted xanthone as a novel primary amine equivalent. The synthesis reduces the number of synthetic steps to the targeted rosamines, for convenient and facile access to potential libraries of rosamine dyes. The prepared rosamine derivatives represent unique multifunctional platforms that possess radiolabeling capability and fluorescence. Rosamines have (i) useful non-specific binding properties in mammalian cells and plant root hair, and (ii) positive uptake or binding properties in microbial systems.

The total synthesis of paracaseolide A, a valuable cell-cycle progression inhibitor, was accomplished in 8 steps from known compounds, with 6.6% overall yield. The synthetic strategy creates strong potential for diversification.

The Diels–Alder reaction of methyl coumalate with alkenes bearing electron-withdrawing groups provides terephthalates or isophthalates in good yields, with the regioselectivity depending on the electron-withdrawing group. The reaction of methyl coumalate with the salt of acrylic acid gave only the monoester of isophthalic acid. Density functional theory (B3LYP/6-31 + G(d,p)) computations of the energies of the competing transition states of the para-selective Diels–Alder reactions are in good agreement with experiment. The surprising regioselectivity of methyl coumalate with activated alkenes is attributed to a secondary orbital interaction between the pyrone oxygen and the dienophile LUMO, which switches the regiochemistry expected from simple frontier molecular orbital theory arguments.

The conversion of readily available 2-halobenzaldehydes into indolo[2,1-a]isoquinolines in two operations represents a very direct entry to this class of molecules.

An inverse electron-demand Diels–Alder reaction between methyl coumalate and electron-rich dienophiles produces substituted benzoates. A high-yielding, single-pot procedure transforms readily accessible vinyl ether, ketal, or orthoester dienophiles into functionalized aromatic systems in a versatile route.

Sulfonate-based anionic surfactants were generated in 2–3 steps from fructose by conversion of fructose to a furan followed by generation of the sulfonate.

5-Alkoxymethylfurfural ethers are synthesized directly from fructose using ionic liquids (imidazolium propanesulfonic acids) and alcohols in a novel biphasic system.

The Lewis acid catalyzed rearrangement of substituted benzyl ethers affords diarylmethanes in good yields. One of the products was converted into a diarylbenzofuran using a benzoylation/P4-tBu cyclization protocol.

2-Formylphenoxy quinones can be converted into xanthones via an acyl radical intermediate with NBS and AIBN.2-Formylphenoxy quinones can be converted into xanthones via an acyl radical intermediate with NBS and AIBN.

The annulation of 2-(nitromethyl)benzoates with enones gave 4-nitro-1-naphthols in good yields. The carbocyclic framework of the stealthins was synthesized.

The Diels–Alder reaction of coumalic acid and methyl coumalate with unactivated alkenes provides only para-substituted adducts in good yield.

The reaction of phenols with 7a led to the synthesis of aurones, while the reaction of phenols with 7b led to the synthesis of flavones.

A flexible synthesis of the azafluorenone alkaloids 1, 2, 3, and 4 is described.

The effects of substituents on the aryl ring were studied by the preparation and testing of several PD173955 analogs. Inserting a single carbon atom into the C–N bond in the aniline subunit (PDC) reduced the kinase inhibition by a factor of 200. Despite its decreased affinity for Abl compared with PD173955, PDC exhibits a Ki very similar to that reported for Imatinib. Increased water solubility is also gained by replacing the thiomethyl group with an amino or glycyl moiety. For both PD173955 and PDC, the analogs with amino groups in place of the methylthio group are 10 times more inhibitory than the parent molecules. Two molecules were identified with Kis about three orders of magnitude lower than reported for Imatinib.The preparation and testing of several PD173955 analogs is described. Despite its decreased affinity for Abl compared with PD, the PDC analog exhibits a Ki very similar to that reported for Imatinib.

A formal synthesis of indolequinoline alkaloid neocryptolepine and isocryptolepine is described which employed a common intermediate and used an intramolecular Wittig reaction followed by regioselective methylation in excellent yield.A formal synthesis of indolequinoline alkaloid neocryptolepine and isocryptolepine is described which employed a common intermediate and used an intramolecular Wittig reaction followed by regioselective methylation in excellent yield.

Dihydroindolo[2,1-a]isoquinolines were synthesized from tetrahydroisoquinolines and α-fluoroaldehydes by a novel two-step procedure. These compounds exhibited significant immunosuppressive activity against IL-2, IL-10 and IFN-γ.Dihydroindolo[2,1-a]isoquinolines were synthesized from tetrahydroisoquinolines and α-fluoroaldehydes by a novel two-step procedure. These compounds exhibited significant immunosuppressive activity against IL-2, IL-10 and IFN-γ.

The reaction of substituted (2-aminobenzyl)triphenylphosphonium bromides with aromatic aldehydes or α,β-unsaturated aldehydes constitutes a new synthesis of 2,3-disubstitued indoles in high yields. The adduct from 4-oxo-3,4-dihydroquinazoline-2-carbaldehyde was an advanced intermediate in the synthesis of several rutaecarpines.

An aldol condensation and an Algar−Flynn−Oyamada oxidative cyclization were key steps in the direct synthesis of chrysosplenol D, an efflux pump inhibitor that can potentiate the activity of commercially important antibiotics and antimalarials.

Littorachalcone (1) and diacid 10 were synthesized by direct routes. The antibacterial activity of 1, 10 and synthetic precursors were evaluated. Dialdehyde 3a showed potent antibacterial activity.Littorachalcone (1) and diacid 10 were synthesized by direct routes. The antibacterial activity of 1, 10 and synthetic precursors were evaluated. Dialdehyde 3 (R = pivaloyl) showed potent antibacterial activity.