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. Subsequent intramolecular Friedel–Crafts reaction affords (hetero)­aryl-fused cyclohexa-1,3-dienes in up to 97% yield. This approach represents the first example of catalysis for this intramolecular, dehydrative ring-opening cyclization and outperforms the previous reports using stoichiometric Lewis acids

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. Regiospecific arylation occurs at the α-carbon of the oxyallyl cation due to polarization caused by the ester group

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. Under dilute reaction conditions with stoichiometric SnCl₄ and at reduced temperatures, an unusual formal [3 + 2]-cycloaddition between the allylsilane and the oxyallyl cation occurred to give hexahydrobenzofuran products in up to 69% yield

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. In these cases, benzenoid products are formed in up to 98% yield. Strategic choice of the substitution about the ACP allows for the generation of other useful isomeric products in good yields

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

The total synthesis of the <i>Strychnos</i> 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 (<b>2</b>). 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 (<b>2</b>) in high yield. A palladium-catalyzed enolate coupling reaction was then used to furnish the final E ring and complete the total synthesis of (±)-minfiensine (<b>2</b>)

α‑Alkylidene-γ-butyrolactone Formation via Bi(OTf)₃‑Catalyzed, Dehydrative, Ring-Opening Cyclizations of Cyclopropyl Carbinols: Understanding Substituent Effects and Predicting <i>E</i>/<i>Z</i> Selectivity

A Bi­(OTf)₃-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 <i>E</i>-isomers. Mechanistically, Bi­(OTf)₃ serves as a stable and easy to handle precursor to TfOH. TfOH then catalyzes the formation of cyclopropyl carbinyl cations, which undergo ring opening, intramolecular trapping by the neighboring ester group, subsequent hydrolysis, and loss of methanol resulting in the formation of the ABLs. The nature and relative positioning of the substituents on both the carbinol and the cyclopropane determine both chemo- and stereoselective outcomes. Carbinol substituents determine the extent of cyclopropyl carbinyl cation formation. The cyclopropane donor substituents determine the overall reaction chemoselectivity. Weakly stabilizing or electron-poor donor groups provide better yields of the ABL products. In contrast, copious amounts of competing products are observed with highly stabilizing cyclopropane donor substituents. Finally, a predictive model for <i>E</i>/<i>Z</i> selectivity was developed using DFT calculations

Cineraria indet.

A Catalytic Homo-Nazarov Cyclization Protocol for the Synthesis of Heteroaromatic Ring-Fused Cyclohexenone

A Catalytic Homo-Nazarov Cyclization Protocol for the Synthesis of Heteroaromatic Ring-Fused Cyclohexenones

A Catalytic Homo-Nazarov Cyclization Protocol for the Synthesis of Heteroaromatic Ring-Fused Cyclohexenone

A Tandem, Bicatalytic Continuous Flow Cyclopropanation-Homo-Nazarov-Type Cyclization

Continuous flow processing represents an emerging technology in the chemical and pharmaceutical industries. Herein, we describe a tandem, bicatalytic continuous flow cyclopropanation-homo-Nazarov-type ring-opening cyclization to form hydropyrido­[1,2-<i>a</i>]­indoles, which represents a naturally occurring chemical scaffold present in many bioactive and therapeutically relevant molecules. The tandem flow reactions provided high conversions (>97%) with product throughputs on the order of 3–5 g h^–1. The individual transformations (cyclopropanation and ring-opening cyclization) were separately optimized in the batch then successfully transferred to the flow. Significantly, this represents the first literature example of continuous flow cyclopropane ring-opening cyclizations; hydropyrido­[1,2-<i>a</i>]­indoles are formed on a multigram scale (>4 g h^–1 throughput) in near-quantitative yields from <i>N</i>-indolyl-1,1-cyclopropyl β-amidoesters. Overall, the continuous flow technology exhibited superior yields, relative to the batch reactions, for both the ring-opening cyclizations and the tandem, bicatalytic reactions. These results provide the basis for large-scale implementation of bicatalytic cyclopropanation-ring-opening cyclization reactions for complex synthesis and represent initial efforts toward the development of an industrially viable, four-step continuous flow synthesis of hydropyrido­[1,2-<i>a</i>]­indoles

Ligands for Glaucoma-Associated Myocilin Discovered by a Generic Binding Assay

Mutations in the olfactomedin domain of myocilin (myoc-OLF) are the strongest link to inherited primary open angle glaucoma. In this recently identified protein misfolding disorder, aggregation-prone disease variants of myocilin hasten glaucoma-associated elevation of intraocular pressure, leading to vision loss. Despite its well-documented pathogenic role, myocilin remains a domain of unknown structure or function. Here we report the first small-molecule ligands that bind to the native state of myoc-OLF. To discover these molecules, we designed a general label-free, mix-and-measure, high throughput chemical assay for restabilization (CARS), which is likely readily adaptable to discover ligands for other proteins. Of the 14 hit molecules identified from screening myoc-OLF against the Sigma-Aldrich Library of Pharmacologically Active Compounds using CARS, surface plasmon resonance binding studies reveal three are stoichiometric ligand scaffolds with low micromolar affinity. Two compounds, GW5074 and apigenin, inhibit myoc-OLF amyloid formation <i>in vitro</i>. Structure–activity relationship-based soluble derivatives reduce aggregation <i>in vitro</i> as well as enhance secretion of full-length mutant myocilin in a cell culture model. Our compounds set the stage for a new chemical probe approach to clarify the biological function of wild-type myocilin and represent lead therapeutic compounds for diminishing intracellular sequestration of toxic mutant myocilin