Modular Enantioselective Total Syntheses of the -7,9-Dihydroxy- and 9-Hydroxy-7-Keto-8,4'-Oxyneolignans.

A modular, enantioselective approach to access the bioactive 7,9-dihydroxy- and 9-hydroxy-7-keto-8,4'-oxyneolignans is disclosed, which employs stereoselective Mitsunobu reactions of enantiopure 2-aryl-1,3-dioxan-5-ols and functionalized phenols. The enantiopure dioxanols are prepared through Sharpless asymmetric dihydroxylation of protected coniferyl or sinapyl alcohols and subsequent benzylidene acetal formation. Through a mix-and-match coupling approach, six of the eight possible -7,9-dihydroxy-8,4'-oxyneolignan enantiomeric natural products (bearing a C-1' hydroxypropyl chain) were generated following sequential deprotection.

Zr-Catalyzed Synthesis of Tetrasubstituted 1,3-Diacylpyrroles from -Acyl α-Aminoaldehydes and 1,3-Dicarbonyls.

A Zr-catalyzed synthesis of tetrasubstituted 1,3-diacylpyrroles is reported that employs the direct use of -acyl α-aminoaldehydes with 1,3-dicarbonyl compounds. The products were formed in up to 88% yield and shown to be hydrolytically and configurationally stable under the reaction conditions (THF/1,4-dioxane and HO). The -acyl α-aminoaldehydes were readily prepared from the corresponding α-amino acids.

Photolysis of Gas-Phase Atmospherically Relevant Monoterpene-Derived Organic Nitrates.

Organic nitrates (ONs) can impact spatial distribution of reactive nitrogen species and ozone formation in the atmosphere. While photolysis of ONs is known to result in the release of NO back to the atmosphere, the photolysis rate constants and mechanisms of monoterpene-derived ONs (MT-ONs) have not been well constrained. We investigated the gas-phase photolysis of three synthetic ONs derived from α-pinene, β-pinene, and d-limonene through chamber experiments.

Lewis Acid-Catalyzed 2,3-Dihydrofuran Acetal Ring-Opening Benzannulations toward Functionalized 1-Hydroxycarbazoles.

The development of a Lewis acid-catalyzed, intramolecular ring-opening benzannulation of 5-(indolyl)2,3-dihydrofuran acetals is described. The resulting 1-hydroxycarbazole-2-carboxylates are formed in up to 90% yield in 1 h. The dihydrofuran acetals are readily accessed from the reactions of enol ethers and α-diazo-β-indolyl-β-ketoesters.

Discovery of 8-Hydroxyquinoline as a Histamine Receptor 2 Blocker Scaffold.

Histamine receptor 2 (HR) activation in the stomach results in gastric acid secretion, and HR blockers are used for the treatment of peptidic ulcers and acid reflux. Over-the-counter HR blockers carry a five-membered aromatic heterocycle, with two of them additionally carrying a tertiary amine that decomposes to N-nitrosodimethylamine, a human carcinogen. To discover a novel HR blocker scaffold to serve in the development of next-generation HR blockers, we developed an HR-based sensor in yeast by linking human HR activation to cell luminescence.

Intramolecular, Interrupted Homo-Nazarov Cascade Biscyclizations to Angular (Hetero)Aryl-Fused Polycycles.

Herein, a SnCl -catalyzed intramolecular, interrupted homo-Nazarov cascade biscyclization to access angular (hetero)aryl-fused polycycles is reported. Subsequent decarboxylation of the readily enolizable products afforded the angular products in up to 71 % yield over two steps, with the trans-diastereomers as the major products. The cyclopropyl homo-Nazarov cyclization precursors were formed using a scalable and modular synthetic route that, ultimately, offers access to 6,6,6-, 6,6,5-, 6,5,6-, 6,6,5,6-, and 6,6,6,5-fused angular polycyclic products.

Synthetic methodology-enabled discovery of a tunable indole template for COX-1 inhibition and anti-cancer activity.

Establishing structure-activity relationships (SAR) for privileged pharmacophores, such as the indole scaffold, is a key step in the early stages of drug discovery. Herein, we report the synthesis and preliminary SAR studies on substituted 6-hydroxyindole-7-carboxylates as a tunable framework for COX inhibition and anti-cancer activity. To facilitate the SAR discovery, a modular synthetic methodology was employed which enabled the synthesis of the substituted indoles.

Completion of the Set: Synthesis of the (6,X')-Flubromazepam Positional Isomers as Standards for Forensic Analysis.

Mounting concern among forensic examiners regarding the emergence of positional isomers as technically legal alternatives to scheduled benzodiazepines has encouraged the preemptive synthesis of analogues as standards. Recently, flubromazepam was identified by the Drug Enforcement Administration for future scheduling, and subsequently, 9 of the 12 possible flubromazepam isomers were synthesized. However, the three (6,X')-isomers proved inaccessible via that approach.

Synthesis and Hydrolysis of Atmospherically Relevant Monoterpene-Derived Organic Nitrates.

The partition of gas-phase organic nitrates (ONs) to aerosols and subsequent hydrolysis are regarded as important loss mechanisms for ON species. However, the hydrolysis mechanisms and the major factors controlling the hydrolysis lifetime are not fully understood. In this work, we synthesized seven monoterpene-derived ONs and systematically investigated their hydrolysis in bulk solutions at different pH values.

Catalyst-Controlled Chemodivergent Reactions of 2-Pyrrolyl-α-diazo-β-ketoesters and Enol Ethers: Synthesis of 1,2-Dihydrofuran Acetals and Highly Substituted Indoles.

A catalyst-controlled, chemodivergent reaction of pyrrolyl-α-diazo-β-ketoesters with enol ethers is reported. While Cu(II) catalysts selectively promoted a [3 + 2] cycloaddition to provide pyrrolyl-substituted 2,3-dihydrofuran (DHF) acetals, dimeric Rh(II) catalysts afforded 6-hydroxyindole-7-carboxylates via an unreported [4 + 2] benzannulation. The choice of enol ether proved to be crucial in determining both regioselectivity and yield of the respective products (up to 91% yield for Cu(II) and 82% for Rh(II) catalysis).

Conversion of Unprotected Aldose Sugars to Polyhydroxyalkyl and -Glycosyl Furans via Zirconium Catalysis.

An efficient, zirconium-catalyzed conversion of unprotected aldose sugars with acetylacetone to polyhydroxyalkyl furans or -glycosylfurans is reported. The furan products are formed in up to 93% yield using 5-10 mol % ZrCl. Pentoses are readily converted at room temperature, while hexoses and their oligosaccharides require mild heating (i.

Elucidation of a Sequential Iminium Ion Cascade Reaction Triggered by a Silica Gel-Promoted Aza-Peterson Reaction.

In a recent methodological study investigating the synthesis of -alkoxyazomethine ylides, an unexpected aminal byproduct was generated during our attempt to isolate -benzyl--((trimethylsilyl)methyl)hydroxylamine. After a strategic investigation, silica gel was discovered to be the cause of the byproduct formation. Through the mechanistic insight from control and trapping experiments, we propose the formation of a methaniminium ion via a novel aza-Peterson reaction, which ultimately triggers a sequential iminium ion cascade sequence.

Chiral disulfonimides: a versatile template for asymmetric catalysis.

Since the emergence of pseudo-C2-symmetric chiral phosphoric acids (CPA), much work has been done to utilize these systems in stereoselective, organocatalytic processes. Despite the success in this field, reasonably basic substrates such as imines are often required to achieve appreciable activation. In order to access a wider variety of potential reaction partners, many related organocatalysts with enhanced Brønsted acidity have since been developed.

Calcium-Catalyzed Formal [5 + 2] Cycloadditions of Alkylidene β-Ketoesters with Olefins: Chemodivergent Synthesis of Highly Functionalized Cyclohepta[]indole Derivatives.

The calcium-catalyzed, formal [5 + 2] cycloaddition of indolyl alkylidene β-ketoesters with mono- and disubstituted aryl olefins to form cyclohepta[]indole derivatives has been established. Unanticipated chemodivergence with phenyl vinyl sulfide/ether revealed a double [5 + 2] cycloaddition cascade providing ethano-bridged cyclohepta[]indoles. Overall, the method's highlights include: (1) use of a green, calcium-based catalyst (2.

Synthesis of Flubromazepam Positional Isomers for Forensic Analysis.

Designer benzodiazepines have recently appeared in many forensic cases as legal alternatives to federally scheduled drugs such as diazepam (Valium) and alprazolam (Xanax). Though current forensic instrumental techniques are often sufficient for identifying novel psychoactive substances, they may not readily differentiate between potential positional isomers. Additionally, characterization data for positional isomers of known designer benzodiazepines are widely nonexistent.

Base-Mediated Cascade Aldol Addition and Fragmentation Reactions of Dihydroxyfumaric Acid and Aromatic Aldehydes: Controlling Chemodivergence via Choice of Base, Solvent, and Substituents.

The diester derivative of dihydroxyfumaric acid (DHF) has been used exclusively as an electrophile in organic synthesis. However, the synthetic utility of DHF's nucleophilic reactivity, contained in the ene-diol moiety, has been underexplored. Inspired by recently observed pH-dependent chemodivergent nucleophilic aldol reactions of dihydroxyfumarate (DHF) with glyoxylate and formaldehyde, we report herein the control and synthetic application of base-controlled chemodivergent reactions between dihydroxyfumarate and aromatic and heteroaromatic aldehydes.

α-Alkylidene-γ-butyrolactone Formation via Bi(OTf)-Catalyzed, Dehydrative, Ring-Opening Cyclizations of Cyclopropyl Carbinols: Understanding Substituent Effects and Predicting E/Z Selectivity.

A Bi(OTf)-catalyzed ring-opening cyclization of (hetero)aryl cyclopropyl carbinols to form α-alkylidene-γ-butyrolactones (ABLs) is reported. This transformation represents different chemoselectivity from previous reports that demonstrated formation of (hetero)aryl-fused cyclohexa-1,3-dienes upon acid-promoted cyclopropyl carbinol ring opening. ABLs are obtained in up to 89% yield with a general preference for the E-isomers.

Rh -Catalyzed β-C(sp )-H Alkylation of Enol Ethers, Enamides and Enecarbamates with α-Diazo Dicarbonyl Compounds.

A Rh -catalyzed method for intermolecular alkylation of the β-C(sp )-H bond of enol ethers, enamides, and enecarbamates with α-diazo-1,3-dicarbonyl compounds is reported. The products are formed in up to 99 % yield and can be readily derivatized under a variety of conditions. By utilizing a combination of experimental and computational studies, the presumptive addition-elimination reaction mechanism was investigated and found to proceed under thermodynamic control at higher temperature.

IMDAF Cascade Approach toward the Synthesis of the Alkaloid (±)-Minfiensine.

The total synthesis of the Strychnos alkaloid (±)-minfiensine was achieved via an intramolecular amidofuran Diels-Alder cycloaddition/rearrangement followed by an iminium ion/cyclization cascade sequence. This domino process provides for a rapid access to the unique 1,2,3,4-tetrahydro-9a,4a-iminoethanocarbazole core structure found in the alkaloid minfiensine (2). In this paper, the full account of our synthetic study is described, highlighting the successful application of the cascade sequence to form the A/B/C/D rings of (±)-minfiensine (2) in high yield.

Catalytic, Interrupted Formal Homo-Nazarov Cyclization with (Hetero)arenes: Access to α-(Hetero)aryl Cyclohexanones.

The first examples of a Lewis-acid catalyzed (hetero)arene interrupted, formal homo-Nazarov cyclization have been disclosed. Using SnCl4 as the catalyst, alkenyl cyclopropyl ketones undergo ring-opening cyclization to form six-membered cyclic oxyallyl cations. Subsequent intermolecular Friedel-Crafts-type arylation with various electron-rich arenes and heteroarenes provides functionalized α-(hetero)arylated cyclohexanones, a scaffold present in many natural products and bioactive compounds, in yields up to 88% and diastereomeric ratios up to 12:1.

Calcium-Catalyzed, Dehydrative, Ring-Opening Cyclizations of Cyclopropyl Carbinols Derived from Donor-Acceptor Cyclopropanes.

A calcium-catalyzed, dehydrative, ring-opening cyclization of (hetero)aryl cyclopropyl carbinols is reported. The cyclopropyl carbinols are prepared directly from the corresponding donor-acceptor (D-A) cyclopropanes. The calcium catalyst catalyzes the formation of putative (hetero)aryl cyclopropyl carbinyl cations that undergo ring-opening to allylcarbinyl cations.

Catalytic, Cascade Ring-Opening Benzannulations of 2,3-Dihydrofuran O,O- and N,O-Acetals.

An Al(OTf)3 -catalyzed intramolecular cascade ring-opening benzannulation of 2,3-dihydrofuran O,O- and N,O-acetals is described. The cascade sequence involves the dihydrofuran ring-opening by acetal hydrolysis, an intramolecular Prins-type cyclization, and aromatization to generate an array of benzo-fused (hetero)aromatic systems in up to 95 % yield. This method represents the first example of dihydrofuran acetal usage in benzannulation reactions.

Catalysis and chemodivergence in the interrupted, formal homo-Nazarov cyclization using allylsilanes.

A chemodivergent, Lewis acid catalyzed allylsilane interrupted formal homo-Nazarov cyclization is disclosed. With catalytic amounts of SnCl4 and in the presence of allyltrimethylsilane, a formal Hosomi-Sakurai-type allylation of the oxyallyl cation intermediate is observed. A variety of functionalized donor-acceptor cyclopropanes and allylsilanes were shown to be amenable to the reaction transformation and the allyl products were formed in up to 92% yield.

A catalytic diastereoselective formal [5+2] cycloaddition approach to azepino[1,2-a]indoles: putative donor-acceptor cyclobutanes as reactive intermediates.

A catalytic formal [5+2] cycloaddition approach to the diastereoselective synthesis of azepino[1,2-a]indoles is reported. The reaction presumably proceeds through a Lewis acid catalyzed formal [2+2] cycloaddition of an alkene with an N-indolyl alkylidene β-amide ester to form a donor-acceptor cyclobutane intermediate, which subsequently undergoes an intramolecular ring-opening cyclization. Azepine products are formed in up to 92% yield with high degrees of diastereoselectivity (up to 34:1 d.

Catalytic, formal homo-Nazarov-type cyclizations of alkylidene cyclopropane-1,1-ketoesters: access to functionalized arenes and heteroaromatics.

A catalytic, formal homo-Nazarov-type cyclization of alkylidene cyclopropanes (ACPs) to give functionalized arenes and heteroaromatics is reported. In the presence of a Lewis acid catalyst, the ACP 1,1-ketoesters undergo distal bond cleavage to afford an allyl cation intermediate. Adjacent π-attack on the allyl cation then provides a six-membered ring that undergoes rapid aromatization.