Interrupted SNAr-Alkylation Dearomatization.

Dearomatizations provide powerful synthetic routes to rapidly assemble substituted carbocycles and heterocycles found in a plethora of bioactive molecules. Harnessing the advantages of dearomatization typically requires vigorous reagents because of the difficulty in disrupting the stable aromatic core. A relatively mild dearomatization strategy is described that employs lithiated nitriles or isocyanides in a simple SNAr-type addition to form σ-complexes that are trapped by alkylation. The dearomatizations are diastereoselective and efficient and rapidly install two new carbon-carbon bonds, one of which is a quaternary center, as well as nitrile, isocyanide, and cyclohexadiene functionalities.

Heterocycles via SiCl4-Promoted Isocyanide Additions to Oxonitriles.

SiCl4 promotes isocyanide additions to oxoalkenenitriles to selectively generate 3-acylpyrroles, 2-aminofurans, or pyrrolidinones. Cyclic oxoalkenenitriles add 2 equiv of an isocyanide that installs the two core atoms of an acylpyrrole and a nitrile substituent, whereas acyclic oxoalkenenitriles add 1 equiv of an isocyanide to afford 2-aminofurans; subsequent air oxidation generates pyrrolidinones via a furan oxygenation-cleavage-cyclization sequence. The syntheses proceed under mild conditions to rapidly access three richly decorated heterocycles.

Polar-Radical Cyclization Cascades with Magnesiated Nitriles.

Naphthalene converts magnesiated ω-alkenylnitriles into bi- and tricyclic ketones via a polar-radical addition-cyclization cascade. One-electron oxidation of magnesiated nitriles generates nitrile-stabilized radicals that cyclize onto a pendant olefin and then rebound onto the nitrile through a reduction-cyclization sequence; subsequent hydrolysis affords a diverse array of bicyclo[3.2.0]heptan-6-ones. Combining the polar-radical cascade with a 1,2:1,4-carbonyl-conjugate addition generates complex cyclobutanones containing four new carbon-carbon bonds and four chiral centers in one synthetic operation.

One-Pot Syntheses of Substituted Oxazoles and Imidazoles from the Isocyanide Asmic.

Substituted oxazoles and imidazoles are synthesized in one pot from the isocyanide building block Asmic (anisylsulfanylmethyl isocyanide), an alkyl halide, and an acid chloride or nitrile, respectively. The modular assembly employs sequential deprotonation-alkylation and deprotonation-acylation or imination of Asmic, followed by an unusual carbon-sulfur bond cleavage to construct the azole. The strategy is robust, highly efficient, and affords C4-C5 disubstituted oxazoles or imidazoles in a single operation.

Chromosome-level genome sequence of the Genetically Improved Farmed Tilapia (GIFT, Oreochromis niloticus) highlights regions of introgression with O. mossambicus.

BACKGROUND: The Nile tilapia (Oreochromis niloticus) is the third most important freshwater fish for aquaculture. Its success is directly linked to continuous breeding efforts focusing on production traits such as growth rate and weight. Among those elite strains, the Genetically Improved Farmed Tilapia (GIFT) programme initiated by WorldFish is now distributed worldwide. To accelerate the development of the GIFT strain through genomic selection, a high-quality reference genome is necessary. RESULTS: Using a combination of short (10X Genomics) and long read (PacBio HiFi, PacBio CLR) sequencing and a genetic map for the GIFT strain, we generated a chromosome level genome assembly for the GIFT. Using genomes of two closely related species (O. mossambicus, O. aureus), we characterised the extent of introgression between these species and O. niloticus that has occurred during the breeding process. Over 11 Mb of O. mossambicus genomic material could be identified within the GIFT genome, including genes associated with immunity but also with traits of interest such as growth rate. CONCLUSION: Because of the breeding history of elite strains, current reference genomes might not be the most suitable to support further studies into the GIFT strain. We generated a chromosome level assembly of the GIFT strain, characterising its mixed origins, and the potential contributions of introgressed regions to selected traits.

Stereoselective Synthesis of (E)- and (Z)-Isocyanoalkenes.

(E)- and (Z)-isocyanoalkenes were selectively synthesized via the sequential cross coupling of vinyl iodides with formamide, followed by dehydration. The optimal catalyst, generated in situ from CuII and trans-N,N'-dimethyl-1,2-cyclohexanediamine, rapidly coupled (E)- or (Z)-vinyl iodides with formamide, which minimized the isomerization of the resultant vinyl formamide. The method efficiently provided a range of acyclic, carbocyclic, and heterocyclic isocyanoalkenes; the versatility is illustrated with the selective, stereodivergent syntheses of the diastereomeric isocyanoalkene antibiotics, B371 and E-B371.

Dearomatization of aromatic asmic isocyanides to complex cyclohexadienes.

A dearomatization-dislocation-coupling cascade rapidly transforms aromatic isocyanides into highly functionalized cyclohexadienes. The facile cascade installs an exceptional degree of molecular complexity: three carbon-carbon bonds, two quaternary stereocenters, and three orthogonal functionalities, a cyclohexadiene, a nitrile, and an isocyanide. The tolerance of arylisocyanides makes the method among the mildest dearomatizations ever reported, typically occurring within minutes at -78 °C. Experimental and computational analyses implicate an electron transfer-initiated mechanism involving an unprecedented isocyanide rearrangement followed by radical-radical anion coupling. The dearomatization is fast, proceeds via a complex cascade mechanism supported by experimental and computational insight, and provides complex, synthetically valuable cyclohexadienes.

Sunk-Cost Bias and Knowing When to Terminate a Research Project.

Scientific research is an open-ended quest where success usually triumphs over failure. The tremendous success of science obscures the tendency for the non-linear discovery process to take longer and cost more than expected. Perseverance through detours and past setbacks requires a significant commitment that is fueled by scientific optimism; the same optimism required to overcome challenges simultaneously exacerbates the very human tendency to continue a line of inquiry when the likelihood of success is minimal, the so-called sunk-cost bias. This Viewpoint Article shows how the psychological phenomenon of sunk-cost bias influences medicinal, pharmaceutical, and organic chemists by comparing how the respective industrial and academic practitioners approach sunk-cost bias; a series of interviews and illustrative quotes provide a rich trove of data to address this seldom discussed, yet potentially avoidable research cost. The concluding strategies recommended for mitigating against sunk-cost bias should benefit not only medicinal, pharmaceutical, and organic chemists but a wide array of chemistry practitioners.

Oxidative DMSO Cyclization Cascade to Bicyclic Hydroxyketonitriles.

Thermolysis of ω-iodoalkyl-ß-siloxyalkenenitriles in DMSO triggers an oxidative cyclization cascade that affords highly oxygenated hydrindanones, decalones, and undecanones. The cyclization cascade is highly unusual on three counts: the cyclization installs a contiguous array of tertiary-quaternary-tertiary centers, thermolysis equilibrates a quaternary center, and the enolsilyl ether crossed-aldol proceeds without a catalyst.

Copper-Catalyzed Conjugate Additions to Isocyanoalkenes.

A copper iodide-Pyox complex catalyzes the first conjugate addition of diverse sulfur, nitrogen, and carbon nucleophiles to isocyanoalkenes. The anionic addition generates metalated isocyanoalkanes capable of SNi displacements, providing a rapid route to a series of functionalized, cyclic isocyanoalkanes. The Cu(I)I-Pyox complex efficiently catalyzes a first-in-class conjugate addition affording a range of complex, functionalized isocyanoalkanes that are otherwise challenging to synthesize while laying a foundation for catalytic reactions that maintain the isocyanide group.

One-step synthesis of imidazoles from Asmic (anisylsulfanylmethyl isocyanide).

Substituted imidazoles are readily prepared by condensing the versatile isocyanide Asmic, anisylsulfanylmethylisocyanide, with nitrogenous π-electrophiles. Deprotonating Asmic with lithium hexamethyldisilazide effectively generates a potent nucleophile that efficiently intercepts nitrile and imine electrophiles to afford imidazoles. In situ cyclization to the imidazole is promoted by the conjugate acid, hexamethyldisilazane, which facilitates the requisite series of proton transfers. The rapid formation of imidazoles and the interchange of the anisylsulfanyl for hydrogen with Raney nickel make the method a valuable route to mono- and disubstituted imidazoles.

Oxazole Synthesis by Sequential Asmic-Ester Condensations and Sulfanyl-Lithium Exchange-Trapping.

Oxazoles are rapidly assembled through a sequential deprotonation-condensation of Asmic, anisylsulfanylmethylisocyanide, with esters followed by sulfanyl-lithium exchange-trapping. Deprotonating Asmic affords a metalated isocyanide that efficiently traps esters to afford oxazoles bearing a versatile C-4 anisylsulfanyl substituent. Interchange of the anisylsulfanyl substituent is readily achieved through a first-in-class sulfur-lithium exchange-electrophilic trapping sequence whose versatility is illustrated in the three-step synthesis of the bioactive natural product streptochlorin.

Metalated isocyanides: formation, structure, and reactivity.

Metalated isocyanides are highly versatile organometallics. Central to the reactivity of metalated isocyanides is the presence of two orthogonally reactive carbons, a highly nucleophilic "carbanion" inductively stabilized by a carbene-like isocyanide carbon. The two reactivities are harnessed in the attack of metalated isocyanides on π-electrophiles where an initial nucleophilic attack leads to an electron pair that cyclizes onto the terminal isocyanide carbon in a rapid route to diverse, nitrogenous heterocycles. Harnessing the potent nucleophilicity of metalated isocyanides while preventing electrophilic attack on the terminal isocyanide carbon has largely been driven by empirical heuristics. This review provides a foundational understanding by surveying the formation, structure, and properties of metalated isocyanides. The focus on the interplay between the structure and reactivity of metalated isocyanides is anticipated to facilitate the development and deployment of these exceptional nucleophiles in complex bond constructions.

Asmic Isocyanide [3 + 2] Cascade to Dihydrooxazoles and Dihydroimidazoles.

The versatile isocyanide building block Asmic, anisylsulfanylmethylisocyanide, reacts with aldehydes and ketones in a BF3·OEt2-mediated condensation to afford thioimidoyl-substituted 2,5-dihydrooxazoles. The condensation is distinguished from related base and transition-metal-catalyzed [3 + 2] processes in proceeding via the condensation of aldehydes and ketones with 2 equiv of an isocyanide followed by a molecular rearrangement that installs four new bonds. BF3·OEt2 mediates an analogous condensation of Asmic with imines to generate N-substituted dihydroimidazoles. Mechanistically, BF3·OEt2 activates the isocyanide to facilitate deprotonation evolving to a zwitterion that traps π-electrophiles in a formal [3 + 2] process. A second deprotonation-condensation with Asmic initiates a structural rearrangement involving a sulfanyl elimination-addition transposition sequence. The resulting dihydrooxazoles and dihydroimidazoles contain a thioimidate that serves as a diversification point for further elaboration.

Acetonitrile-Hexane Extraction Route to Pure Sulfonium Salts.

A rapid, simple procedure is described for synthesizing trialkyl, dialkylaryl, and alkyldiaryl sulfonium salts that features a selective extraction procedure to access analytically pure sulfonium salts. Alkylation of dialkylsulfides, alkylarylsulfides, and diarylsulfides followed by partitioning between acetonitrile and hexanes efficiently separates nonpolar reactants and byproducts, the usual impurities, to afford analytically pure crystalline and noncrystalline sulfonium salts. The method is efficient, general, and particularly well suited for the preparation of oily sulfonium salts that are otherwise extremely difficult to purify.

In-Vitro Evaluation of Cardiac Energetics and Coronary Flow with Volume Displacement and Rotary Blood Pumps.

Bridge to recovery with left ventricular assist device (LVAD) support has been more prominent with volume displacement pumps (VDPs) than with rotary blood pumps (RBPs), which may be due to VDPs providing greater ventricular unloading and coronary artery flow. To compare ventricular unloading and coronary flow of VDPs and RBPs in a repeatable environment, a physiologic coronary circulation was added to a pre-existing mock circulatory loop. In this study, a physiologic coronary circulation, mimicking a healthy or diseased auto-regulatory response was implemented in a mock circulatory loop. Using the mock circulation loop, a VDP with original (Björk-Shiley) and then replacement (jellyfish) valves was operated in clinically recommended modes and compared to full and partial assist RBP operating at constant speed and rapid speed modulated modes. The Björk-Shiley VDP resulted in increased pressure-volume area, which resulted in greater coronary artery flow when compared to the improved jellyfish valves. Full assist RBP support reduced left ventricular stroke work, pressure-volume area and coronary flow compared to partial assist, whilst the effect of speed modulation modes was not as significant. Of all LVAD operating modes, the counter-pulsed VDP with jellyfish valves demonstrated the greatest reduction in pressure-volume area and improved coronary flow. This study provides a basis for further investigation into RBP speed modulation profiles to match the improved haemodynamic performance of VDPs.

Asmic: An Exceptional Building Block for Isocyanide Alkylations.

Asmic addresses the long-standing challenge of alkylating isocyanides, providing access to isocyanides with diverse substitution patterns. The o-anisylsulfanyl group serves a critical dual role by facilitating deprotonation-alkylation and providing a latent nucleophilic site through an unusual arylsulfanyl-lithium exchange.

Evidence for functional state transitions in intensively-managed soil ecosystems.

Soils are fundamental to terrestrial ecosystem functioning and food security, thus their resilience to disturbances is critical. Furthermore, they provide effective models of complex natural systems to explore resilience concepts over experimentally-tractable short timescales. We studied soils derived from experimental plots with different land-use histories of long-term grass, arable and fallow to determine whether regimes of extreme drying and re-wetting would tip the systems into alternative stable states, contingent on their historical management. Prior to disturbance, grass and arable soils produced similar respiration responses when processing an introduced complex carbon substrate. A distinct respiration response from fallow soil here indicated a different prior functional state. Initial dry:wet disturbances reduced the respiration in all soils, suggesting that the microbial community was perturbed such that its function was impaired. After 12 drying and rewetting cycles, despite the extreme disturbance regime, soil from the grass plots, and those that had recently been grass, adapted and returned to their prior functional state. Arable soils were less resilient and shifted towards a functional state more similar to that of the fallow soil. Hence repeated stresses can apparently induce persistent shifts in functional states in soils, which are influenced by management history.

Electrophile-Dependent Alkylations of Lithiated 4-Alkoxyalk-4-enenitriles.

Alkylations of acyclic, lithiated 4-alkoxyalk-4-enenitriles are highly diastereoselective with an unusual electrophile-dependent preference. Alkyl halides, sulfur, chlorine, and acyl cyanide electrophiles intercept a series of lithiated 4-alkoxyalk-4-enenitriles to install contiguous tertiary-quaternary stereocenters with high diastereoselectivity, whereas acylations with ester and carbonate electrophiles are modestly selective. The diastereoselectivity is consistent with electrophilic attack on the most accessible face of the lithated nitrile for most electrophiles except ester and carbonate electrophiles, which likely precoordinate the lithiated nitrile before acylation. Intercepting the lithiated 4-alkoxyalk-4-enenitriles with a range of electrophiles provide insight into the criteria for otherwise challenging diastereoselective alkylations and acylations of acyclic nitriles.

Electrophile-Directed Diastereoselective Oxonitrile Alkylations.

Diastereoselective alkylation of prochiral oxonitrile dianions with secondary alkyl halides efficiently installs two contiguous stereogenic centers. The confluence of nucleophilic trajectory and the electrophile chirality causes distinct steric differences that allow efficient discrimination for one of the six possible conformers. Numerous oxonitrile-derived dianions efficiently displace secondary alkyl halides propagating the electrophile chirality to efficiently install two contiguous tertiary centers. The prevalence of chiral, secondary electrophiles makes the interdigitated alkylation of chiral electrophiles a particularly attractive route because the resulting oxonitriles are readily transformed into bioactive heterocycles.