Synthesis of Fused Tricyclic Amines Bearing Tetrasubstituted Carbons Using an Alkylation-Cyclization-Isomerization-3-aza-Cope Cascade Reaction.

A new cascade reaction sequence that involves alkylation, cyclization, isomerization, and 3-aza-Cope rearrangement was discovered. The stereogenic centers of the starting piperidines were transferred to the bicyclic enamine products, and a range of electron-withdrawing groups on the alkyne moieties, from ketones to amides, were tolerated under the reaction conditions. The bicyclic enamines underwent trifluoroacetic acid (TFA)-mediated cyclization to form tricyclic amines bearing tetrasubstituted carbons.

p-Methoxy- and 2,4-Dimethoxybenzyl N-Acetylcarbamate Potassium Salts: Versatile Reagents for N-Alkylacetamide and p-Methoxy- and 2,4-Dimethoxybenzyl Carbamates.

The acetamide moiety is a general functional group present in many natural and pharmaceutical products. Herein, we report two new reagents, p-methoxybenzyl N-acetylcarbamate potassium salt (PM-BENAC-K) and 2,4-dimethoxybenzyl N-acetylcarbamate potassium salt (2,4-DM-BENAC-K), which are refined versions of the benzyl N-acetylcarbamate potassium salt (BENAC-K). These compounds, which we reported as simple equivalents of N-acetamide nucleophiles, are stable and easy-to-handle powders that react with a variety of alkyl halides and sulfonates to afford substituted products in good yields. The products were transformed into N-alkylacetamides after p-methoxybenzyloxycarbonyl (Moz) or 2,4-dimethoxybenzyloxycarbonyl (Dmoz) cleavage under mild acidic conditions. The acetyl groups in the substituted products of PM- and 2,4-DM-BENAC-Ks were removed using K2CO3 in methanol to afford Moz- and Dmoz-protected amines, respectively. Hence, the new BENAC-Ks acted as versatile equivalents of both N-acetamide and Moz/Dmoz-protected nitrogen nucleophiles and can be used in synthetic studies of natural and pharmaceutical products.

Biomimetic Construction of a syn-2,7-Dimethyloxepane Ring via 7-Endo Cyclization.

syn-2,7-Dimethyloxepane is a unique structure observed in natural ladder-shaped polycyclic ethers (LSPs), such as Caribbean ciguatoxins, gymnocin-B, and brevisulcenal-F that exhibit potent biological activities. Thus, the successful construction of this seven-membered ring is desirable, but its ring strain and the 1,3-repulsion between its two methyl groups makes this process difficult. Herein, we prepared syn-2,7-dimethyloxepanes via 7-endo cyclizations of vinyl epoxides that break Baldwin's rules. Such a biomimetic approach to syn-2,7-dimethyloxepanes has not yet been reported; however, we achieved this challenging cyclization with the aid of a cis-olefin tether and an unsubstituted vinyl group. The NO-ring fragment of gymnocin-B was also prepared from one of these 7-endo cyclized products, demonstrating the potential application of this strategy in constructing bioactive LSPs.

Gold(I)-Catalyzed Cyclization-3-Aza-Cope-Mannich Cascade and Its Application to the Synthesis of Cephalotaxine.

The discovery of a new gold(I)-catalyzed cascade reaction involving cyclization onto a vinylammonium, 3-aza-Cope rearrangement, and Mannich cyclization is reported. A variety of fused nitrogen heterocycles were prepared from simple cyclic tertiary amines using 1-5 mol % of a AuCl(PPh3)/Ag[C5(CN)5] cocatalyst system. The developed reaction was used in a study aimed at synthesizing cephalotaxine. A five-step operation from norhydrastinine provided demethylcephalotaxinone in 39.1% overall yield, which was transformed to (-)-cephalotaxine in two steps.

Synthesis of the GHIJKL Fragment of Gymnocin-B.

The GHIJKL fragment of gymnocin-B was synthesized using the oxiranyl anion strategy. The first highlight of the synthesis is the bromoketone cyclization reaction on the oxepane ring to construct the fused bisoxepane GH ring. The second key step is the introduction of the trans-4-hydroxy-3-methyloxepane J ring via addition of trimethylaluminum to a conjugated oxonium moiety, followed by diastereoselective epoxidation and regioselective reduction.

Ion-Pair Extraction of Quaternary Ammoniums Using Tetracyanocyclopentadienides and Synthetic Application for Complex Ammoniums.

A simple isolation method for quaternary ammonium cations via ion-pair extraction using tetracyanocyclopentadienide (TCCP) was established. Separation of tetraethylammonium and carbachol cations was achieved by the selective extraction of tetraethylammonium with ethoxycarbonyl TCCP, which was moderately lipophilic. The ion-pair extraction with TCCPs was applied to the synthesis of complex quaternary ammonium salts, including a spiro vinylammonium that is a precursor of the novel 3-aza-Cope-Mannich cascade.

Aza Diels-Alder Reactions of Nitriles, N,N-Dimethylhydrazones, and Oximino Ethers. Application in Formal [2 + 2 + 2] Cycloadditions for the Synthesis of Pyridines.

Metal-free, formal [2 + 2 + 2] cycloaddition strategies for the synthesis of polycyclic pyridine derivatives are described. The overall transformation proceeds via a two-stage pericyclic cascade mechanism. In the first step, an intramolecular propargylic ene reaction generates a vinylallene that is necessarily locked in the s-cis conformation. This vinylallene exhibits exceptional reactivity as a Diels-Alder reaction partner and engages in [4 + 2] cycloadditions with normally unreactive azadienophiles including unactivated cyano groups and heterosubstituted imine derivatives such as dimethylhydrazones and oximino ethers. Few examples of oximino ether Diels-Alder reactions have been reported previously, and normal electron-demand [4 + 2] cycloadditions of unactivated dialkylhydrazones are unprecedented. Overall, this metal-free formal [2 + 2 + 2] cycloaddition provides access to polycyclic pyridine derivatives and complements transition-metal-catalyzed [2 + 2 + 2] strategies.

Convergent Synthesis of Fused Ring Systems in Large Polycyclic Ethers.

This article reviews our studies on the oxiranyl anion-based, [X+2+Y]-type convergent strategy for the synthesis of polycyclic ether natural products. The strategy is noteworthy for its flexibility, which allows for the generation of different-sized fused ring systems based on a ring expansion reaction. For a precise understanding of this key ring expansion, we first focused on the reaction mechanism, in which an equatorial attack of TMS-diazomethane was determined to be the crucial step. In the later part of this review, the application of our oxiranyl anion-based strategy to large fused ring systems is described. The advantageous flexibility is highlighted in the divergent synthesis of five octacyclic ethers involving the CDEFGHIJ-ring skeleton of yessotoxin and its ring-modified analogs. Total synthesis of gymnocin-A was achieved using the oxiranyl anion convergent strategy, which furnished its large system of fourteen contiguous ether rings.

Synthesis of the KLMN Fragment of Gymnocin-A from the FGH Fragment.

An improved route for the synthesis of the KLMN fragment of gymnocin-A was developed through the oxiranyl anion coupling of the FGH fragment with a chiral C3 epoxy sulfone, followed by 6-endo cyclization. This straightforward approach reduced the number of synthetic steps by 14 compared with a previous route using alternative building blocks.

CAr-O Rotamers in 3,3'-Disubstituted BINOL Esters.

Rotamers around the CAr-O bond were disclosed in 3,3'-disubstituted BINOL esters by NMR spectroscopy. A bulky R1 group increased the rotational barrier. The pivalate showed two rotamers at 2 °C, and broad signals were observed close to room temperature when R2 = Ph. The highest rotational barrier was recorded for the (tetracyanocyclopentadienyl)carboxylate, and C-O rotamers were present at room temperature. DFT calculations indicated the presence of repulsion between R1 and R2 during rotation of the CAr-O bond.

Methanolysis of the Cyclic Acetal Function of NanoKid Catalyzed by NanoGoblin, the Pyridinium Salt of Tetracyanocyclopentadienide.

Small, "doll"-shaped tetracyanocyclopentadienide bearing a 1,3-dioxane acetal "head" and cyano "hands" and "feet" was synthesized. Its pyridinium salt, which was named NanoGoblin, exhibited catalytic activity in the methanolysis of acetals, as demonstrated by the reaction with NanoKid in methanol-d 4, where the acetal head of NanoKid was converted to a deuterated dimethyl acetal moiety.

Correction to "Methanolysis of the Cyclic Acetal Function of NanoKid Catalyzed by NanoGoblin, the Pyridinium Salt of Tetracyanocyclopentadienide".

[This corrects the article DOI: 10.1021/acsomega.7b01748.].

Acceleration of Acid-Catalyzed Hydrolysis in a Biphasic System by Sodium Tetracyanocyclopentadienides.

The hydrolysis of tert-butyldimethylsilyl L-menthyl ether (3) in a CH2Cl2-1 M HCl biphasic solvent system was accelerated by the addition of sodium tetracyanocyclopentadienides 1. Particularly, the reaction rate was enhanced using sodium salt 1a-c with a lipophilic substituent on the cyclopentadienide ring. From the results obtained by a triphasic experiment, hydrolysis proceeds via the formation of hydronium ion 2 in the aqueous phase by ion exchange, followed by the transfer of 2 to the CH2Cl2 phase.

Total Synthesis of Brevisamide Using an Oxiranyl Anion Strategy.

A total synthesis of brevisamide, a marine monocyclic ether amide isolated from the dinoflagellate Karenia brevis, has been achieved in 18 steps starting from 4-(benzyloxy)butanol. The synthesis involves oxiranyl anion coupling between an epoxy sulfone and a triflate, intramolecular etherification of a hydroxy-bromoketone, diastereoselective introduction of the axial methyl group by hydroxyl-directed hydrogenation of an exocyclic olefin, and installation of an acetamide side chain by nucleophilic substitution of an N-acetyl carbamate. The dienal side chain is assembled using a Horner-Wadsworth-Emmons reaction to complete the synthesis.

Molecular epidemiological tracing of a cattle rabies outbreak lasting less than a month in Rio Grande do Sul in southern Brazil.

BACKGROUND: Vampire bat-transmitted cattle rabies cases are typically encountered in areas where the disease is endemic. However, over the period of a month in 2009, an outbreak of cattle rabies occurred and then ended spontaneously in a small area of the Rio Grande do Sul State in southern Brazil. To investigate the epidemiological characteristics of this rabies outbreak in Rio Grande do Sul, 26 nucleotide sequences of rabies virus (RABV) genomes that were collected in this area were analyzed phylogenetically. RESULTS: Nucleotide sequence identities of the nucleoprotein gene and G-L intergenic region of the 26 RABVs were greater than 99.6 %. Phylogenetic analysis showed that all RABVs clustered with the vampire bat-related cattle RABV strains and that the RABVs were mainly distributed in southern Brazil. CONCLUSIONS: The findings of the present study suggested that a small population of rabid vampire bats carrying a single RABV strain produced a spatiotemporally restricted outbreak of cattle rabies in southern Brazil.

Total Synthesis of Gymnocin-A.

A convergent total synthesis of cytotoxic marine natural polycyclic ether, gymnocin-A (1), is described. The synthesis features three iterations of an oxiranyl anion strategy, involving base-mediated cycloetherification, ring expansion, and reductive etherification, for the construction of the FGH fragment and for its coupling with the ABC and KLMN fragments.

Establishing conditions for the storage and elution of rabies virus RNA using FTA(®) cards.

The Flinders Technology Associates filter paper cards (FTA(®) cards) can be used to store nucleic acid from various samples and are easily portable. However, RNA is physicochemically unstable compared with DNA, and appropriate methods have not been established for storage and extraction of RNA from FTA(®) cards. The present study investigated the optimum conditions for storage and elution of viral RNA (vRNA) using rabies virus (RABV) applied to FTA(®) cards. When TE buffer was used, the elution rates of vRNA increased with the length of the elution time. When the cards were stored at -80 °C or -20 °C, vRNA was stable over 3 months. Degradation of vRNAs occurred following storage at 4 °C and room temperature, suggesting that RNA should be extracted from cards as soon as possible if no freezer is available. When we tried to amplify vRNA from RABV-infected animal brains applied to FTA(®) cards and stored at -80 °C for 6 months, we did not detect any amplified products with the primer set for 964 bp of RABV N gene. However, we were able to detect amplified products by increasing the elution time of vRNA from FTA(®) cards from 30 min to 24 hr or by changing the primer sets to amplify 290 bp of N gene. Thus, we recommend extending the elution time for damaged or low concentration samples in FTA(®) cards.

Synthesis of the KLMN fragment of gymnocin-A using oxiranyl anion convergent methodology.

Synthesis of the KLMN fragment of gymnocin-A has been achieved by a [X + 2 + Y]-type convergent strategy involving the coupling of a K-ring triflate and an N-ring epoxy sulfone. Fusions of the L ring and the M ring were carried out by intramolecular SN2 substitution of a tertiary alcohol and reductive etherification to furnish the target molecule.

Easy-to-use rapid gene amplification method for direct detection of RNA and DNA viruses in sera and feces from various animals.

The development of rapid and simple gene amplification tests is required for detection of pathogens to prevent transmission of infectious diseases between animals or from animals to humans. An easy-to-use rapid gene amplification method that can directly detect RNA and DNA viruses in clinical samples was developed. This method is based on combining loop-mediated isothermal amplification (LAMP) or reverse transcription-LAMP (RT-LAMP) and RNA GEM Tissue, a thermophilic enzyme that extracts nucleic acid by quickly digesting proteins and ribonucleases. The authors named these methods GEM LAMP and GEM RT-LAMP. These methods were able to detect viral DNA and RNA within 70 min in a single tube using only a water bath. The detection capacities were 10-100-fold more sensitive than those of previously established LAMP and RT-LAMP methods. The GEM LAMP and GEM RT-LAMP methods were used to detect macroscopically the presence of DNA and RNA viruses in sera or fecal samples from cattle, pigs, horses, dolphins, penguins, and sea lions using SYBR green I. The GEM LAMP and GEM RT-LAMP methods thus have considerable versatility as tools for detecting pathogens and are applicable to basic human and veterinary medicine, environmental hygiene, and point-of-care-testing.

Synthesis of functionalized tetracyanocyclopentadienides from tetracyanothiophene and sulfones.

Tetracyanothiophene and tetracyano-1,4-dithiin react with a leaving group substituted carbon nucleophile such as ethyl benzenesulfonylacetate to afford substituted tetracyanocyclopentadienyl sodium derivatives in moderate to high yields through a putative condensation and desulfurization pathway. Subsequent functional-group transformation reactions on the Cp anion ring provided various C5R(CN)4(-) derivatives.