Syntheses of differentially protected isocoumarins

Syntheses of an isocoumarin subunit suitable for the completion of purpuromycin are outlined. Specifically, work targeting an orthogonally protected isocoumarin (eventually 12% yield over 12 steps) and an improved synthesis of a symmetrically protected isocoumarin (18% over 10 steps) are described. A new modification for selective catechol protection as mediated by potassium bicarbonate is also presented along with insights into oxidative and reductive functionalization of isocoumarins.     

Alternative spiroketalization methods toward purpuromycin: a diketone approach to prevent benzofuran formation

The central portion of purpuromycin has been assembled via a classical spiroketalization reaction. Key to promoting this reaction mode versus benzofuran formation was the oxidation state of the spiroketal core. With a higher oxidation state, even the electron-deficient isocoumarin found in purpuromycin could be employed directly in the spiroketalization. The two halves of the spiroketalization precursor were joined via a nitrile oxide/styrene 1,3-dipolar cycloaddition. A very mild selenium dioxide oxidation was used to introduce the required oxidation state of the spiroketal core.     

Regioselective cyclization of 2-alkynylbenzoic acid in water for the synthesis of isocoumarin

In this work, a regioselective synthesis of isocoumarins from 2-alkynylbenzoic acid is reported. The transformations proceed smoothly with good yields in water via a metal-free radical pathway. When catalytic TBAB is employed, the reaction provides various isocoumarin derivatives according to the structures of the corresponding precursors. It is believed that TBAB serves as a phase transfer catalyst and radical initiator in the reaction. Compared to previous methodologies, the synthetic procedure reported herein provides a more environmentally benign route for the synthesis of isocoumarins.     

Rh(III)-catalyzed C-H activation of primary benzamides and tandem cyclization with cyclic 2-diazo-1,3-diketones for the synthesis of isocoumarins

A simple and efficient Rh(III)-catalyzed C-H activation and tandem intramolecular cyclization for the synthesis of isocoumarins has been developed. The protocol uses easily available primary benzamides and cyclic 2-diazo-1,3-diketones as starting materials. This reaction proceeds via C-C and C-O bond formation in a single reaction vessel, and the corresponding isocoumarins were obtained in moderate to excellent yields (58%–97%). The well established protocol showed high functional group tolerance, which provided an efficient and alternative route to isocoumarin backbone.     

Synthesis of 3-substituted isocoumarins and their inhibitory effects on degranulation of RBL-2H3 cells induced by antigen

Eleven 3-substituted isocoumarins and a benzylidenephthalide were synthesized through thermal cyclization reaction of delta- and gamma-ketoamides, respectively. Subsequent deprotection of the hydroxyl groups of the resulting isocoumarin and benzylidenephthalide compounds afforded thunberginols A, B, and F, respectively, which originated from the processed leaves of Hydrangea macrophylla SERINGE var. thunbergii MAKINO. The synthesized isocoumarins and thunberginols were evaluated for their anti-allergic activity, in which thunberginol B exhibited the highest inhibitory potency on the degranulation of RBL-2H3 cells induced by antigen. Structure-activity relationship studies were carried out to determine the necessary substituents on the 3-phenylisocoumarin skeleton for inhibitory activity.     

Synthesis and antimicrobial activities of some isocoumarin and dihydroisocoumarin derivatives

A new series of the isocoumarin derivatives of ibuprofen, fluribiprofen, naproxen, valproic acid and 1-naphthoic acid have been synthesized via condensation of homophthalic acid with their respective acid chlorides. The conversion of the latter two isocoumarins into (dl)-3,4-dihydroisocoumarins has also been achieved. Most of the synthesized compounds showed antifungal and antibacterial activities.     

Synthesis of Heterocycles by Formal Cycloadditions of Isocyanides

Synthetic methodology for the synthesis of heterocycles is of continuous and high interest with applications in materials, catalysis, and medicines. Multicomponent reactions are suitable tools to efficiently generate chemically diverse sets of heterocycles with sufficient structural complexity. Especially isocyanides have proven to be particularly versatile building blocks in these one‐pot processes. Due to their electronic structure, isocyanides are able to act sequentially or simultaneously as a nucleophile and an electrophile. Traditionally, isocyanides are therefore frequently used in multicomponent chemistry. In the recent literature, numerous reactions have been reported that involve formal cycloadditions of isocyanides with conjugated heterodienes. This Focus Review aims at mapping this reactivity and at providing insight into the relationship between the various reported reaction partners and the observed reactivity modes.     

Identification of Claisen cyclase domain in fungal polyketide synthase WA, a naphthopyrone synthase of Aspergillus nidulans

BACKGROUND: Based on the homology with fatty acid synthases and bacterial polyketide synthases (PKSs), thioesterase domains have been assigned at the C-terminus regions of fungal iterative type I PKSs. We previously overexpressed Aspergillus nidulans wA PKS gene in a heterologous fungal host and identified it to encode a heptaketide naphthopyrone synthase. In addition, expression of C-terminus-modified WA PKS gave heptaketide isocoumarins suggesting that the C-terminus region of WA PKS is involved in the cyclization of the second aromatic ring of naphthopyrone. To unravel the actual function of the C-terminus region, we carried out functional analysis of WA PKS mutants by C-terminus deletion and site-directed mutagenesis. RESULTS: Only the 32 amino acid deletion from the C-terminus of WA PKS caused product change to heptaketide isocoumarins from heptaketide naphthopyrone, YWA1 1, a product of intact WA PKS. Further C-terminus deletion mutant of WA PKS up to Ser(1967), an active site residue of so far called thioesterase, still produced isocoumarins. Site-directed mutagenesis of amino acid residues in this C-terminus region showed that even a single mutation of S1967A or H2129Q caused production of isocoumarin instead of naphthopyrone. Furthermore, the role of tandem acyl carrier proteins (ACPs), a typical feature of fungal aromatic PKSs, was examined by site-directed mutagenesis and the results indicated that both ACPs can function as ACP independently. CONCLUSIONS: Claisen-type cyclization is assumed to be involved in formation of aromatic compounds by some fungal type I PKSs. These PKSs have a quite identical architecture of active site domain organization, beta-ketoacyl synthase, acyltransferase, tandem ACPs and thioesterase (TE) domains. Since the C-terminus region of WA PKS of this type was determined to be involved in Claisen-type cyclization of the second ring of naphthopyrone, we propose that the so far called TE of these PKSs work not just as TE but as Claisen cyclase.     

Assembly of 3-substituted isocoumarins via a CuI-catalyzed domino coupling/addition/deacylation process

An efficient strategy for the synthesis of a variety of 3-substituted isocoumarins has been developed. The reaction proceeded from o-halobenzoic acids and 1,3-diketones via a copper(I)-catalyzed domino reaction in DMF under the action of K(3)PO(4) at 90-120 °C without a ligand to afford the corresponding 3-substituted isocoumarin derivatives in good to excellent yields. o-Halobenzoic acids could be o-iodobenzoic acid, o-bromobenzoic acid, and o-chlorobenzoic acid derivatives. 1,3-Diketones could be alkyl- and aryl-substituted 1,3-diketones.     

Bioactive isocoumarins from a terrestrial Streptomyces sp. ANK302

Four isocoumarins have been isolated from the terrestrial Streptomyces sp. ANK302, namely 6,8-dimethoxy-3-methylisocoumarin (1), 6,8-dihydroxy-3-methylisocoumarin (2), 6,8-dihydroxy-7-methoxy-3-methylisocoumarin (3), and 6,7,8-trimethoxy-3-methylisocoumarin (4). Compound 1 is a new naturally-occurring isocoumarin, and 2 was isolated as a new bacterial product. The structures 1-4 were deduced from high resolution mass, 1D and 2D NMR spectra and by comparison with related compounds from the literature. Compound 2 showed a strong zoosporicidal activity at a concentration of 5 microg/mL against a phytopathogenic oomycete, Plasmopara viticola, and 1 was active against     

A Convergent Total Synthesis of the Telomerase Inhibitor (±)‐γ‐Rubromycin

The total synthesis of the human telomerase inhibitor γ‐rubromycin in its racemic form was accomplished in 3.8 % overall yield. The key feature of this synthesis is an efficient acid‐catalyzed spiroketalization for the construction of the spiroketal core. The required electronically well‐balanced spiroketal precursor was obtained by the convergent assembly of a naphthyl‐substituted aldehyde, an α‐methoxyallyl‐γ‐silyl‐substituted phosphonate as the central C₃ building block, and a highly functionalized aryl Grignard reagent. Another key feature is the late‐stage construction of the isocoumarin moiety and a simultaneous protodesilylation furnishing the known methyl aryl ether protected precursor of γ‐rubromycin.     

Indium-Catalyzed C−F Bond Transformation through Oxymetalation/β-Fluorine Elimination to Access Fluorinated Isocoumarins

Fluorinated heterocycles have attracted much attention in the pharmaceutical and agrochemical industries. Many strategies have already been developed to achieve the synthesis of fluorinated heterocycles. Formidable challenges remain, however, in the synthesis of fluorinated isocoumarin derivatives that are among the most alluring structural motifs. Herein, the indium-catalyzed C−F bond transformation of 2-(2,2-difluorovinyl) benzoates is reported, which are readily accessible compounds, to give a diverse array of fluorinated isocoumarins. The present reaction proceeds smoothly using inexpensive reagents: a catalytic amount of indium salt in the presence of zinc salt. A theoretical calculation of potential energy profiles showed that the reaction consists of oxymetalation with the elimination of alkyl halide and the β-fluorine elimination.     

NHC-catalyzed oxidative cyclization reactions of 2-alkynylbenzaldehydes under aerobic conditions: synthesis of O-heterocycles

An NHC-catalyzed, regio- and stereoselective oxidative cyclization of o-alkynylbenzaldehydes bearing an unactivated alkyne moiety as an internal electrophile has been developed to afford phthalides and isocoumarins. A single organocatalytic system enabled two sequential C-O bond formations to take place in an atom economical manner via highly efficient dual activation. Molecular oxygen in air could be utilized as a source of an oxygen atom for the oxidation of aldehydes to the corresponding benzoic acids under our newly developed reagent system.     

Convergent route to the purpuromycin bisphenolic spiroketal: hydrogen bonding control of spiroketalization stereochemistry

A mild and efficient [3+2] nitrile oxide/olefin cycloaddition provided a rapid and convergent entry into precursors of bisphenolic spiroketals, a structural type unique to the rubromycin family of natural products. In addition, implementation of the premise that a hydrogen bond from the C4-OH controls the stereochemistry of the purpuromycin core resulted in moderate diastereocontrol in the spiroketalization. Spectroscopic and X-ray data of these systems have provided the first assignment of the relative configuration of purpuromycin.     

On the Mechanism of Bifunctional Squaramide‐Catalyzed Organocatalytic Michael Addition: A Protonated Catalyst as an Oxyanion Hole

A joint experimental–theoretical study of a bifunctional squaramide‐amine‐catalyzed Michael addition reaction between 1,3‐dioxo nucleophiles and nitrostyrene has been undertaken to gain insight into the nature of bifunctional organocatalytic activation. For this highly stereoselective reaction, three previously proposed mechanistic scenarios for the critical C?C bond‐formation step were examined. Accordingly, the formation of the major stereoisomeric products is most plausible by one of the bifunctional pathways that involve electrophile activation by the protonated amine group of the catalyst. However, some of the minor product isomers are also accessible through alternative reaction routes. Structural analysis of transition states points to the structural invariance of certain fragments of the transition state, such as the protonated catalyst and the anionic fragment of approaching reactants. Our topological analysis provides deeper insight and a more general understanding of bifunctional noncovalent organocatalysis.     

Modified polysulfones. IV. Synthesis and characterization of polymers with silicon substituents for a comparative study of gas‐transport properties

We previously conducted a detailed study of gas‐transport and other properties of a series of silicon derivatives of Udel polysulfone (PSf) and Radel polyphenylsulfone; we now report the details of their preparation by the reaction of lithiated polymer intermediates with chlorosilylalkylaryl electrophiles. Ortho‐sulfone‐substituted polymers with pendant trimethylsilyl, dimethylphenylsilyl, and diphenylmethylsilyl and other groups were obtained by direct metalation followed by the reaction of the dilithiated intermediate with the appropriate silyl electrophile. In addition, the structural regularity and geometry of the dilithiated site was also exploited to introduce silicon into the main chain by the reaction of dichlorosilyl electrophiles, leading to the formation of a new tricyclic heteroatom ring. Ortho‐ether PSf derivatives were obtained from a dibrominated polymer via the lithiation of brominated polymer and reaction with a silyl electrophile. The degree of substitution of the silyl groups was 2.0 or less from dilithiated polymers and was dependent on the electrophile reactivity and reaction conditions. A detailed structural characterization of the polymers by NMR and IR spectroscopy is reported in addition to glass‐transition temperatures and thermal stabilities. © 2001 John Wiley & Sons, Inc. J Polym Sci Part A: Polym Chem 39: 2103–2124, 2001     

Palladium‐Catalyzed Intermolecular Acylation of Aryl Diazoesters with ortho‐Bromobenzaldehydes

In this work, we describe a palladium‐catalyzed intermolecular O acylation of α‐diazoesters with ortho‐bromobenzaldehydes. The C(sp²)?H bond activation of the aldehyde is enabled by migratory insertion of a palladium carbene intermediate. The diazoesters act as modular three‐atom units to build up key seven‐membered palladacycles, which are transformed into a variety of isocoumarin derivatives upon reductive elimination. Mechanistic experiments and DFT calculations provide insight into the reaction pathway.     

Cooperative, highly enantioselective phosphinothiourea catalysis of imine-allene [3 + 2] cycloadditions

A new family of phosphinthiourea catalysts was developed for the highly enantioselective synthesis of 2-aryl-2,5-hydropyrroles via a [3 + 2] cycloaddition of an electron-deficient allene with aryl and heteroaryl diphenylphosphinoylimines. The presence of both H2O and Et3N as additives was found to be important for achieving optimal rates. Dual activation of both nucleophile and electrophile by the bifunctional catalyst is invoked to account for the observed high reactivity and enantioselectivity.     

Curtin-Hammett paradigm for stereocontrol in organocatalysis by diarylprolinol ether catalysts

Detailed mechanistic study of two reactions catalyzed by diarylprolinol ether catalysts, the conjugate addition of aldehydes to nitro-olefins and the α-chlorination of aldehydes, leads to the proposal that the stereochemical outcome in these cases is not determined by the transition state of the step in which the stereogenic center is formed from enamine attack on the electrophile but instead is correlated with the relative stability and reactivity of diastereomeric intermediates downstream in the catalytic cycle. This combination of kinetic and thermodynamic factors illustrates a remarkable Curtin-Hammett scenario that can result in either an enhancement or an erosion of the selectivity that would be predicted by the transition state for enamine attack on the electrophile. Evidence is offered to suggest that this concept may represent a general phenomenon for pyrrolidine-based catalysts lacking an acidic directing proton. Implications for catalyst and reaction design are discussed.     

Determining the solution state orientation of a Ti enolate via stable isotope labeling, NMR spectroscopy, and modeling studies

Our group has used Ti-promoted aldol additions with an oxazolidineselone as the chiral auxiliary with much success. In these reactions, the Se atom in the auxiliary both promotes stereospecific addition as well as reports on, through the use of 77Se NMR spectroscopy, the ratio of diastereomers produced and the geometry of intermediates as the reaction proceeds. Through stable isotope labeling and NMR spectroscopy, we are able to experimentally observe a Ti enolate in solution and gain insight into its structure and reactivity. Results from molecular modeling calculations are also presented for comparison with NMR data.