Stereoselective Intramolecular [2+2] Trapping of 1,2-Cyclohexadienes: a Route to Rigid, Angularly Fused Tricyclic Scaffolds.

1,2-Cyclohexadienes generated under mild fluoride-mediated desilylative conditions undergo efficient intramolecular [2+2] trapping, providing tricyclic alkylidene cyclobutanes with complete diastereoselectivity for the cis-fused products. Pendent styrenes or electron-deficient olefins can trap simple 1,2-cyclohexadienes or their oxygenated counterparts, with 14 substrates being disclosed. Reactions proceed at ambient temperature using just cesium fluoride in up to 91 % yield, and the necessary precursors are easily accessed from substituted 2-bromocyclohexenones. Multiple synthetic routes have been developed to install the appropriate functional groups required for [2+2] trapping.

Generation and trapping of electron-deficient 1,2-cyclohexadienes. Unexpected hetero-Diels-Alder reactivity.

Keto-substituted 1,2-cyclohexadienes were generated by base-mediated (KOt-Bu) elimination, and found to dimerize via an unprecedented formal hetero-Diels-Alder process, followed by hydration. These highly reactive cyclic allene intermediates were also trapped in Diels-Alder reactions by furan, 2,5-dimethylfuran, or diphenylisobenzofuran to afford cycloadducts with high regio- and diastereoselectivity, and could also be intercepted in a hetero-Diels-Alder process with enamine dienophiles. Endo/exo stereochemistry was unambiguously determined via X-ray crystallography in the case of nitrile-substituted 1,2-cyclohexadiene. DFT calculations indicate that the novel hetero-Diels-Alder processes observed with these allenes occur via a concerted asynchronous cycloaddition mechanism.

One-Pot Generation of Bicyclo[3.1.0]hexanols and Cyclohexanones by Double Interrupted Nazarov Reactions.

Organoaluminum-mediated double interrupted Nazarov cyclization to access bicyclo[3.1.0]hexanols via nucleophilic methyl attack followed by Simmons-Smith-type electrophilic cyclopropanation is reported. These alcohols can undergo ring opening to afford cyclohexanones or cyclohexenones, broadening the range of scaffolds available via interrupted Nazarov reaction beyond the usual cyclopentanoid products. Throughout the sequence, a total of four new C-C bonds are formed, along with four new stereogenic centers.

Dual Catalytic Synthesis of Antiviral Compounds Based on Metallocarbene-Azide Cascade Chemistry.

Aryl azides trap ortho-metallocarbene intermediates to generate indolenones possessing a reactive C-acylimine moiety, which can react with added indole nucleophiles to afford the 2-(3-indolyl)indolin-3-one scaffold found in the antiviral natural product isatisine A. This overall process occurs through a dual catalytic sequence at room temperature. Redox activation of the Cu(OTf)2 precatalyst by indole results in catalytically competent Cu(I) required for azide-metallocarbene coupling. The Brønsted acid that is also formed from Cu(OTf)2 reduction is responsible for catalysis of the C-C bond-forming indole addition step. This modular, procedurally simple method allows for rapid assembly of bis(indole) libraries, several of which proved to have anti-infective activity against respiratory syncytial virus and Zika virus.

Oxidation-Initiated Cyclizations of Pentadienyl Ethers: An Alternative Entry to the Nazarov Reaction.

Oxidation-initiated Nazarov reactions of 1,4-pentadien-3-yl ethers take place in the presence of DDQ. Termination by regioselective elimination preserves both stereocenters created during electrocyclization, providing cyclopentanone products bearing an exocyclic methylene unit. Use of catalytic DDQ with MnO2 as terminal oxidant is also described.

Interrupting the Nazarov Cyclization with Bromine.

The generation of dibrominated cyclopentenones via an interrupted Nazarov cyclization is reported. The installation of two bromine atoms occurs at the α and α' positions of the cyclopentenyl scaffold via successive nucleophilic and electrophilic bromination of the 2-oxidocyclopentenyl cation and its resulting enolate. Notably, the reaction proceeds with good diastereoselectivity, favoring the symmetrical product.

Reactivity and stereoselectivity of 6π and nazarov electrocyclizations of bridged bicyclic trienes and divinyl ketones.

The 6π electrocyclizations and Nazarov cyclizations of a series of bridged bicyclic substrates were modeled with the M06-2X density functional and the def2-TZVPP basis set, and the factors responsible for the reactivities of these substrates and the stereoselectivities of their ring closures were identified. The ring closures of these bridged bicyclic trienes are up to a million-fold faster (ΔΔG(⧧) = 10 kcal mol(-1)) than that of 1,3,5-hexatriene, despite the absence of any activating functional groups. Three effects, preorganization, predistortion, and a CH π interaction, are responsible for this sizable difference in reactivity. Stereoselectivity is partially controlled by torsional effects, but for highly exo selective electrocyclizations, it is reinforced by a second effect (either a CH π interaction or a steric clash). The absence of this second effect in the ring closures of several divinyl ketones explains the reduced selectivity of these ring closures. In one case, a divinyl ketone (ketone 6) undergoes Nazarov cyclization to yield the endo product preferentially. For this example, through-space interaction of a nonconjugated alkene with the divinyl ketone π system in the endo transition state and a steric effect override the intrinsic exo selectivity.

Correction: New fluorinated fructose analogs as selective probes of the hexose transporter protein GLUT5.

Correction for 'New fluorinated fructose analogs as selective probes of the hexose transporter protein GLUT5' by Olivier-Mohamad Soueidan, et al., Org. Biomol. Chem., 2015, 13, 6511-6521.

New fluorinated fructose analogs as selective probes of the hexose transporter protein GLUT5.

Facilitated hexose transporters (GLUTs) mediate the transport of hexoses and other substrates across the membranes of numerous cell types, and while some are expressed ubiquitously (e.g., GLUT1), others are more tissue specific (e.g., GLUT5). These properties have been exploited for the imaging of cancer cells by the use of hexose based probes, including fluorinated hexose derivatives for use with positron emission tomography (PET). However, design of new probes has been hampered by a limited understanding of how GLUT transporters interact with their substrates at the molecular level. Two fluorinated fructose surrogates designed for uptake by the GLUT5 transporter are described here: 3-deoxy-3-fluoro-D-fructose (3-FDF) and 1-deoxy-1-fluoro-2,5-anhydromannitol (1-FDAM). Synthesis (both cold and radiolabeled) and in vitro analysis of their transport characteristics in two breast cancer cell lines (EMT-6 and MCF-7) expressing GLUT5 are detailed. Both analogues are readily taken up into both cancer cell lines, with uptake mediated primarily by GLUT5. They also have low IC50 values, indicating a high affinity for the transporter, suggesting that the uptake of these probes would be unaffected by endogenously circulating fructose. Selective uptake by GLUT5 was also demonstrated in Xenopus oocytes. Finally, these results are the first demonstration that a hexose existing predominantly in the pyranose ring structure (3-FDF) is transported by GLUT5, strongly suggesting that this transporter can handle both furanose and pyranose forms of fructose.

Experimental and computational studies on interrupted Nazarov reactions: exploration of umpolung reactivity at the α-carbon of cyclopentanones.

A set of densely substituted, α-functionalized cyclopentanones can be generated by a two-component, domino reaction sequence entailing the Nazarov electrocyclization of divinyl ketones and nucleophilic addition of the resulting 2-oxidocyclopentenyl cations by selected trapping modalities. Bypassing the typical eliminative termination, Nazarov oxyallyl species can react with carbon π-nucleophiles through cycloadditions (or formal cycloadditions), in which bridged bicyclic systems are established, or nucleophilic trappings whereby one terminal carbon of the oxyallyl intermediate is subjected to carbon-carbon bond formation. A detailed investigation of reaction parameters to explicitly control the course of the "interrupted" Nazarov reactions is described. This methodology allows for facile installation of α-quaternary centers bearing allyl, alkynyl, and heteroaryl groups in an umpolung fashion. In addition, the trapping event of a Nazarov intermediate with furan was studied by DFT computations, in conjunction with experimental data, offering a rationale for the observed reaction pattern and diastereoselectivity.

A strained ring for stereoselective synthesis.

The spring-loaded tension of a cyclic allene expedites synthesis of a natural product.

A Fluorescence-Based Assay to Probe Inhibitory Effect of Fructose Mimics on GLUT5 Transport in Breast Cancer Cells.

Rapid cell division and reprogramming of energy metabolism are two crucial hallmarks of cancer cells. In humans, hexose trafficking into cancer cells is mainly mediated through a family of glucose transporters (GLUTs), which are facilitative transmembrane hexose transporter proteins. In several breast cancers, fructose can functionally substitute glucose as an alternative energy supply supporting rapid proliferation. GLUT5, the principal fructose transporter, is overexpressed in human breast cancer cells, providing valuable targets for breast cancer detection as well as selective targeting of anticancer drugs using structurally modified fructose mimics. Herein, a novel fluorescence assay was designed aiming to screen a series of C-3 modified 2,5-anhydromannitol (2,5-AM) compounds as d-fructose analogues to explore GLUT5 binding site requirements. The synthesized probes were evaluated for their ability to inhibit the uptake of the fluorescently labeled d-fructose derivative 6-NBDF into EMT6 murine breast cancer cells. A few of the compounds screened demonstrated highly potent single-digit micromolar inhibition of 6-NBDF cellular uptake, which was substantially more potent than the natural substrate d-fructose, at a level of 100-fold or more. The results of this assay are consistent with those obtained from a previous study conducted for some selected compounds against 18F-labeled d-fructose-based probe 6-[18F]FDF, indicating the reproducibility of the current non-radiolabeled assay. These highly potent compounds assessed against 6-NBDF open avenues for the development of more potent probes targeting GLUT5-expressing cancerous cells.

2 + 2 Trapping of Acyloxy-1,2-cyclohexadienes with Styrenes and Electron-Deficient Olefins.

Oxygenated-1,2-cyclohexadienes and their unsubstituted counterpart can be generated under mild conditions by fluoride-induced desilylation and undergo intermolecular [2 + 2]-cycloaddition reactions with a variety of alkene traps to afford bicyclo[4.2.0]octenes. Both styrenes and electron-deficient olefins react in good conversion and with complete regioselectivity in favor of cyclobutane formation at the unsubstituted C2/C3 carbons of the C1-substituted cyclic allenes. Diastereoselectivities are modest (1.1-5.7:1) with a preference for the exo-isomer.

Towards Selective Binding to the GLUT5 Transporter: Synthesis, Molecular Dynamics and In Vitro Evaluation of Novel C-3-Modified 2,5-Anhydro-D-mannitol Analogs.

Deregulation and changes in energy metabolism are emergent and important biomarkers of cancer cells. The uptake of hexoses in cancer cells is mediated by a family of facilitative hexose membrane-transporter proteins known as Glucose Transporters (GLUTs). In the clinic, numerous breast cancers do not show elevated glucose metabolism (which is mediated mainly through the GLUT1 transporter) and may use fructose as an alternative energy source. The principal fructose transporter in most cancer cells is GLUT5, and its mRNA was shown to be elevated in human breast cancer. This offers an alternative strategy for early detection using fructose analogs. In order to selectively scout GLUT5 binding-pocket requirements, we designed, synthesized and screened a new class of fructose mimics based upon the 2,5-anhydromannitol scaffold. Several of these compounds display low millimolar IC50 values against the known high-affinity 18F-labeled fructose-based probe 6-deoxy-6-fluoro-D-fructose (6-FDF) in murine EMT6 breast cancer cells. In addition, this work used molecular docking and molecular dynamics simulations (MD) with previously reported GLUT5 structures to gain better insight into hexose-GLUT interactions with selected ligands governing their preference for GLUT5 compared to other GLUTs. The improved inhibition of these compounds, and the refined model for their binding, set the stage for the development of high-affinity molecular imaging probes targeting cancers that express the GLUT5 biomarker.

Olefination of α,α'-divinyl ketones through catalytic Meyer-Schuster rearrangement.

The direct olefination of 1,4-dien-3-ones remains a synthetic challenge. A two-step protocol, employing acetylide addition followed by catalytic Meyer-Schuster rearrangement has been developed for the olefination of 1,4-pentadien-3-ones to afford [3]dendralenes. Many of the traditional methods for the Meyer-Schuster rearrangement of alkynyl carbinols are not suitable with these highly unsaturated substrates because of their acid sensitivity. Unexpected reactivity during attempted rearrangement, including Nazarov-type electrocyclizations, is presented, along with conditions to promote the Meyer-Schuster rearrangement of ethoxyacetylene adducts using catalytic VO(acac)(2).

Brønsted acid-mediated Nazarov cyclization of vinylallenes.

Treatment of siloxy enynes with base leads to the corresponding vinylsiloxyallenes which undergo Nazarov cyclization in the presence of trifluoroacetic acid to provide the cyclized product as a mixture of regioisomers in moderate to good overall yield.

A Mild Method for the Generation and Interception of 1,2-Cycloheptadienes with 1,3-Dipoles.

1,2-Cycloheptadiene is a strained, transient species that has been underutilized as a synthetic building block. Seven-membered cyclic allenes are mostly known for their propensity to undergo rapid dimerization, and relatively little has been reported regarding their cycloaddition reactivity with 1,3-dienes or 1,3-dipoles. This work describes the trapping of 1-acetoxy-1,2-cycloheptadiene and its unsubstituted counterpart, generated via desilylative elimination, with a range of 1,3-dipolar trapping partners, affording complex polycyclic products with high regio- and diastereoselectivity.

Cyclization of cross-conjugated trienes: the vinylogous Nazarov reaction.

Cross-conjugated trienoates can be readily prepared from 1,4-pentadien-3-one precursors via a 2-step process: 1,2-addition of lithiated ethynyl ethyl ether followed by rearrangement of the resulting propargylic alcohol with catalytic VO(acac)(2). Treatment of the trienoates with stoichometric (TiCl(4)) or catalytic (Sc(OTf)(3)) Lewis acid provided conjugated alkylidenecyclopentenes via an apparent vinylogous Nazarov cyclization.

One-carbon ring expansion of azetidines via ammonium ylide [1,2]-shifts: a simple route to substituted pyrrolidines.

Simple N-substituted azetidines were heated with diazocarbonyl compounds in the presence of catalytic Cu(acac)(2) to furnish substituted pyrrolidines via Stevens [1,2]-shift. In all but two examples, complete selectivity was seen for ring expansion rather than migration of the other exocyclic group on the azetidinium nitrogen. The two exceptions, observed with ylides substituted with two carbonyl groups and lacking a stabilizing group at the 2-position of the azetidine, underwent exocyclic benzyl migration in preference to ring expansion.

Strain-Activated Diels-Alder Trapping of 1,2-Cyclohexadienes: Intramolecular Capture by Pendent Furans.

Intramolecular [4 + 2] cycloaddition reactions of substituted 1,2-cyclohexadienes with pendent furans enables the synthesis of complex tetracyclic scaffolds in a single step under mild conditions. All Diels-Alder cycloadducts were obtained as single diastereomers, assigned as the endo isomer. Substrates were easily assembled via Stork-Danheiser alkylation of 3-ethoxy-2-bromocyclohex-2-enone to accommodate a range of tethers and furan traps. Cleavage of enol acetate moieties resulted in room-temperature Diels-Alder cycloreversion to tethered furyl cyclohexenones.