Diastereoselective Pd-catalyzed Decarboxylative (4+2) Cycloaddition Reactions of 4-Vinylbenzoxazinanones and 2-Nitro-1,3-enynes.

A formal palladium-catalyzed decarboxylative (4+2) cycloaddition reaction between 4-vinylbenzoxazinanones and 2-nitro-1,3-enynes has been developed to produce highly valuable, densely functionalized tetrahydroquinolines in moderate to excellent yields with high diastereoselectivity under mild reaction conditions. The optimised protocol tolerates a range of substituted 2-nitro-1,3-enynes, which represent an under-utilized class of dipolarophile for transition-metal catalyzed cycloadditions. The employed reaction methodology facilitates efficient cycloaddition with both N-H- and N-Ts-4-vinylbenzoxazinanone dipole precursors. The stereochemistry of the major and minor diastereomeric (4+2) cycloadducts was determined by single crystal X-ray analyses. A mechanistic rationale for the high intrinsic diastereoselectivity and preliminary enantioselective experiments are also presented. The tetrahydroquinoline cycloadduct products feature numerous pendant functionalities, including a vinyl handle, an internal alkyne motif and a nitro functionality (which functions as a latent C-3 nitrogen substituent) for further synthetic manipulations.

DFT Mechanistic Insights into the Ni(II)-Catalyzed Enantioselective Arylative Cyclization of Tethered Allene-Ketones.

Density functional theory (DFT) has provided a detailed mechanistic picture for the redox neutral nickel(II)-catalyzed arylative cyclization reactions of a tethered allene-ketone with arylboronic acids. A mechanistic rationale for the high diastereo- and enantioselectivity achieved experimentally at high reaction temperature was uncovered through modeling the reaction with a chiral ligand and the predicted stereochemical outcome corroborates with experimental results. An unprecedented mechanism for the base-free organoboron transmetalation was revealed and the regioselectivity of migratory insertion of tethered allene-ketones as well as the stability of the possible allylnickel isomers (σ-allyl vs π-allyl) were clarified. The multifaceted nature of the reaction is revealed with certain elementary steps preferring cationic compared to the neutral state.

Diastereoselective Petasis-Borono-Mannich Crotylation Reactions of Chiral α-Heteroatom (F, OBz, OH) Aldehydes: Rapid Access to Valuable Mono and Bicyclic Heterocyclic Scaffolds.

The crotylation reactions of chiral α-F, α-OBz and α-OH aldehydes under Petasis-borono-Mannich conditions using (E)- or (Z)-crotylboronates and primary amines resulted in γ-addition products in high dr and high er. α-F and α-OBz aldehydes gave 1,2-anti-2,3-syn and 1,2-anti-2,3-anti, products, respectively while an α-OH aldehyde gave 1,2-syn-2,3-syn products. The stereochemical outcomes of reactions of the former aldehydes can be explained using a six-membered ring transition state (TS) model in which a Cornforth-like conformation around the imine intermediate is favoured resulting in 1,2-anti products. The 2,3-stereochemical outcome is dependent upon the geometry of the crotylboronate. These TS models were also supported by DFT calculations. The stereochemical outcomes of reactions employing an α-OH aldehyde can be rationalised as occurring via an open-TS involving H-bonding in the imine intermediate between the α-OH group and the imine N atom. Representative products were converted to highly functionalized 1,2,3,6-tetrahydropyridines and 3H-oxazolo[3,4-a]pyridine-3-ones which will be valuable scaffolds in synthesis.

Synthesis and Atropisomeric Properties of Benzoazepine-Fused Isoindoles.

Atropisomeric, bench-stable benzoazepine-fused isoindoles were synthesized via oxidation from isoindoline precursors. Using the isoindoles 5d-f as models, the stereochemistry and conformational folding of the systems were examined. Chiral UHPLC was used to analyze the rate of racemization and calculate the Gibbs free energy of enantiomerization (ΔG‡Enant). X-ray crystallography, 1H NMR spectroscopy, and DFT calculations were used to elucidate the three axes of chirality and clarify the structural factors contributing to ΔG‡Enant. Tandem rotation around the axes of chirality precludes the formation of diastereomers, with rotational restriction of the Caryl-Nsulfonamide bond determined as the moderator of atropisomeric stability in the system, affected primarily by steric hindrance as well as by π-stacking interactions facilitated by the folded conformation of the sulfonamide over the isoindole moiety.

Palladium-catalysed enantio- and regioselective (3 + 2) cycloaddition reactions of sulfamidate imine-derived 1-azadienes towards spirocyclic cyclopentanes.

An enantio- and diastereoselective Pd-catalysed (3 + 2) cycloaddition of bis(trifluoroethyl) 2-vinyl-cyclopropane-1,1-dicarboxylate (VCP) with cyclic sulfamidate imine-derived 1-azadienes (SDAs) has been developed. These reactions provide highly functionalized spiroheterocycles having three contiguous stereocentres, including a tetrasubstituted carbon bearing an oxygen functionality. The two geminal trifluoroethyl ester moieties can be manipulated in a facially selective manner to afford more diversely decorated spirocycles with four contiguous stereocentres. In addition, diastereoselective reduction of the imine moiety can also afford a fourth stereocentre and exposes the important 1,2-amino alcohol functionality.

Nickel Phosphite-Catalyzed Tetradehydro-Diels-Alder Reactions of (E)-3-ene-1,8-diynes.

A nickel-catalyzed tetradehydro-Diels-Alder reaction of (E)-3-ene-1,8-diynes for the preparation of isoindolines, dihydroisobenzofurans, and tetrahydroisoquinolines has been developed. A series of air-stable nickel catalysts were used in this study, including the novel nickel(0)-phosphite catalysts, Ni[P(O-3,5-Me-Ph)3]4, Ni[P(O-1-naphthyl)3]4, and Ni[P(O-2-naphthyl)3]4. To help understand the type of intermediate in the initial cycloisomerization process, the trapping of nickellacycle intermediates with pinacolborane to yield vinyl boronates is also discussed.

Direct SN2 or SN2X Manifold─Mechanistic Study of Ion-Pair-Catalyzed Carbon(sp3)-Carbon(sp3) Bond Formation.

Density functional theory (DFT) is used in this work to predict the mechanism for constructing congested quaternary-quaternary carbon(sp3)-carbon(sp3) bonds in a pentanidium-catalyzed substitution reaction. Computational mechanistic studies were carried out to investigate the proposed SN2X manifold, which consists of two primary elementary steps: halogen atom transfer (XAT) and subsequent SN2. For the first calculated model on original experimental substrates, XAT reaction barriers were more kinetically competitive than an SN2 pathway and connect to thermodynamically stable intermediates. Extensive computational screening modeling was then done on various substrate combinations designed to study the steric influence and to understand the mechanistic rationale, and calculations reveal that sterically congested substrates prefer the SN2X manifold over SN2. Different halides as leaving groups were also screened, and it was found that the reactivity increases in the order of I > Br > Cl > F, in agreement with the strength of C-X bonds. However, DFT modeling suggests that chlorides can be a viable substrate for the SN2X process, which should be further explored experimentally. ONIOM calculations on the full catalyst model predicted the correct stereochemical outcome, and further catalyst screening with cationic Me4N+ and K+ predicted that pentanidium is still the choice for SN2X C-C bond formation.

Understanding the Influence of Donor-Acceptor Diazo Compounds on the Catalyst Efficiency of B(C6 F5 )3 Towards Carbene Formation.

Diazo compounds have been largely used as carbene precursors for carbene transfer reactions in a variety of functionalization reactions. However, the ease of carbene generation from the corresponding diazo compounds depends upon the electron donating/withdrawing substituents either side of the diazo functionality. These groups strongly impact the ease of N2 release. Recently, tris(pentafluorophenyl)borane [B(C6 F5 )3 ] has been shown to be an alternative transition metal-free catalyst for carbene transfer reactions. Herein, a density functional theory (DFT) study on the generation of carbene species from α-aryl α-diazocarbonyl compounds using catalytic amounts of B(C6 F5 )3 is reported. The significant finding is that the efficiency of the catalyst depends directly on the nature of the substituents on both the aryl ring and the carbonyl group of the substrate. In some cases, the boron catalyst has negligible effect on the ease of the carbene formation, while in other cases there is a dramatic reduction in the activation energy of the reaction. This direct dependence is not commonly observed in catalysis and this finding opens the way for intelligent design of this and other similar catalytic reactions.

Density-dependence and seasonal variation in reproductive output and sporophyte production in the kelp, Ecklonia radiata.

The kelp, Ecklonia radiata, is an abundant subtidal ecosystem engineer in southern Australia. Density-dependent changes in the abiotic environment engineered by Ecklonia may feedback to affect reproduction and subsequent recruitment. Here, we examined: 1) how the reproductive capacity of Ecklonia individuals in the field (zoospores released · mm-2 reproductive tissue) varied with adult density and time, and 2) how the recruitment of microscopic gametophytes and sporophytes was influenced by zoospore density at two times. Zoospore production did not vary with adult density, with only one month out of ten sampled over a 2-y period showing a significant effect of density. However, zoospore production varied hugely over time, being generally highest in mid-autumn and lowest in mid-late summer. There were strong effects of initial zoospore density on gametophyte and sporophyte recruitment with both a minimum and an optimum zoospore density for sporophyte recruitment, but these varied in time. Almost no sporophytes developed when initial zoospore density was <6.5 · mm-2 in spring or <0.5 · mm-2 in winter with optimum densities of 90-355 · mm-2 in spring and 21-261 · mm-2 in winter, which resulted in relatively high recruitment of 4-7 sporophytes · mm-2 . Sporophyte recruitment declined at initial zoospore densities >335 · mm-2 in spring and >261 · mm-2 in winter and was zero at very high zoospore densities. These findings suggest that although adult Ecklonia density does not affect per-capita zoospore production, because there is a minimum zoospore density for sporophyte production, a decline in population-level output could feedback to impact recruitment.

A Rare Alder-ene Cycloisomerization of 1,6-Allenynes.

Thermally induced cycloisomerization reactions of 1,6-allenynes gives α-methylene-γ-lactams via intramolecular Alder-ene reactions. The mechanism is supported by computational and deuterium labelling studies. This thermal, non-radical method enables the discovery of a hitherto unknown route that proceeds via a divergent mechanism distinct from the previous [2+2] cycloisomerization manifold.

The Pd-catalysed asymmetric allylic alkylation reactions of sulfamidate imines.

The Pd-catalysed asymmetric allylic alkylation (Pd-AAA) of prochiral enamide anions derived from 5H-oxathiazole 2,2-dioxides has been developed. Various 4,5-disubstituted and 4-substituted cyclic sulfamidate imines have participated in the transformation with a range of allyl carbonates-as well as 2-vinyl oxirane, 2-vinyl-N-tosylaziridine, and 2-vinyl-1,1-cyclopropane dicarboxylate-to furnish the desired C-allylated products in moderate to high yields, with high regioselectivites and generally high enantioselectivities. Conversion between N- and C-allyl products was observed, with the N-allylated products converting to the C-allylated products over time. The resulting high-value allylated heterocyclic products all bear a tetrasubstituted stereogenic centre and can be reduced to an allylated chiral sulfamidate or an amino alcohol.

Palladium-Catalyzed Formal (3 + 2) Cycloaddition Reactions of 2-Nitro-1,3-enynes with Vinylaziridines, -epoxides, and -cyclopropanes.

A two-step Pd-catalyzed (3 + 2) cycloaddition/HNO2 elimination reaction sequence has been developed to give novel cyclic 1,3-dien-5-yne systems from Pd-stabilized zwitterionic 1,3-dipoles and 2-nitro-1,3-enyne substrates. The process is highly atom-efficient and tolerates the reaction of 2-vinyloxirane, 1-tosyl-2-vinylaziridine, and diethyl 2-vinylcyclopropane-1,1-dicarboxylate derived 1,3-dipoles with a variety of 2-nitro-1,3-enyne substrates. The stereochemistry of the intermediate (3 + 2) cycloadducts was determined by single crystal X-ray analysis. Furthermore, a selective kinetic elimination of the cycloadduct with an antiperiplanar relationship between the NO2 group and the participating hydrogen was demonstrated, allowing for efficient isolation of a single diastereoisomer of the cycloadduct.

Stereogenic and conformational properties of medium-ring benzo-fused N-heterocycle atropisomers.

Medium-ring (7-9-membered) benzo-fused N-heterocycles - a core structure in several important pharmaceuticals - have a diverse range of interesting conformational and stereochemical properties which arise from restricted bond rotation in the non-aromatic ring. The atropisomers of these pharmaceutically relevant N-heterocycles typically exhibit different biological activities, warranting the need to deeply understand the factors controlling the conformation and stereochemistry of the systems. Beginning with a brief introduction to atropisomer classification, this review will detail a number of medium-ring benzo-fused N-heterocycle systems from the recent literature to provide an overview of structural factors which can affect the atropisomeric nature of the systems by altering the overall conformation and rate of stereo-inversion. As well as general factors such as ring-size and sterics, the impact of additional stereocentres in these systems will be addressed. This includes the differences between sulfur, nitrogen and carbon stereocentres, and the consequences of stereocentre placement around the N-heterocycle ring. Further, conformational stabilisation via non-covalent intramolecular bonds will be explored. As such, this review represents a significant resource for aiding in the design, synthesis and study of new and potentially bioactive medium-ring benzo-fused N-heterocycles.

Computational Investigation into the Mechanistic Features of Bromide-Catalyzed Alcohol Oxidation by PhIO in Water.

Iodosobenzene (PhIO) is known to be a potent oxidant for alcohols in the presence of catalytic bromide in water. In order to understand this important and practical oxidation process, we have conducted density functional theory studies to shed light on the reaction mechanism. The key finding of this study is that PhIO is not the reactive oxidant itself. Instead, the active oxidant is hypobromite (BrO-), which is generated by the reaction of PhIO with bromide through an SN2-type reaction. Critically, water acts as a cocatalyst in the generation of BrO- through lowering the activation energy of this process. This investigation also demonstrates why BrO- is a more powerful oxidant than PhIO in the oxidation of alcohols. Other halide additives have been reported experimentally to be less effective catalysts than bromide-our calculations provide a clear rationale for these observations. We also examined the effect of replacing water with methanol on the ease of the SN2 reaction, finding that the replacement resulted in a higher activation barrier for the generation of BrO-. Overall, this work demonstrates that the hypervalent iodine(III) reagent PhIO can act as a convenient and controlled precursor of the oxidant hypobromite if the right conditions are present.

Gold-Catalyzed Conversion of Highly Strained Compounds.

The past decade has witnessed the golden age of homogeneous gold-catalyzed reactions, especially those that involve the transformation of highly strained molecules into complex molecular architectures. Gold catalysts, with unique electronic properties and catalytic abilities, have elevated versatile reaction modes through π-interaction induced activation. On the basis of increasing research interest in this topic, together with the significant development of various ligands, including phosphine ligands and azacyclic or noncyclic carbene ligands, the understanding of the catalytic function of gold catalysts has become much deeper and more comprehensive. Different reaction needs thus could be adapted by a novel gold catalyst with a diversified ligand selection. Furthermore, the whole evolution of the gold catalysis on synthetic methodologies has realized and expanded its application into natural product synthesis as well as the potentiality of drug discovery, which endows this ancient metal with a magnificent renaissance. The reactivity of strained small ring molecules with high tension has always been an important research topic in organic chemistry. When the highly strained small ring is linked with a π-electron rich moiety or contains a heteroatom, the gold activation of the π-system or coordination with the heteroatom can initiate a cascade reaction, usually followed by ring opening or expansion. These processes can result in the rapid construction of complex and distinct molecular structures, many of which feature in biologically important molecules. In this review, we will mainly summarize the advances on diverse reaction types and molecular constructions accomplished by homogeneous gold catalysis using highly strained substrates, including methylenecyclopropanes (MCPs), vinylidenecyclopropanes (VDCPs), cyclopropenes as well as aziridine- and epoxide-containing molecules, focusing on the last 10 years. For functionalized alkynyl cyclopropanes, several early inspiring and elegant examples will be described in this review for systematically understanding these transformations.

Five-membered cyclic sulfamidate imines: versatile scaffolds for organic synthesis.

In recent years, five-membered ring cyclic sulfamidate imines (5H-1,2,3-oxathiazole 2,2-dioxides) have received increasing attention as useful precursors for the stereoselective synthesis of many valuable heterocycles. Bearing a reactive N-sulfonyl imine moiety as part of the stereodefined skeleton, this sulfamidate imine platform has been utilised as a substrate in many reactions, including nucleophilic additions and reductions, to prepare highly functionalised cyclic sulfamidates. In addition, cyclic sulfamidate imines can also readily participate as nucleophiles in many chemical transformations, owing to the acidic proton(s) adjacent to the imine moiety. This short review highlights recent developments involving cyclic sulfamidate imines, including their synthesis and reactivity, with a focus on stereoselective processes.

Rhodium-catalysed tetradehydro-Diels-Alder reactions of enediynes via a rhodium-stabilized cyclic allene.

Efficient methods for the synthesis of fused-aromatic rings is a critical endeavour in the creation of new pharmaceuticals and materials. A direct method for preparing these systems is the tetradehydro-Diels-Alder reaction, however this is limited by the need for harsh reaction conditions. A potential, but underdeveloped, route to these systems is via transition metal-catalysed cycloaromatisation of ene-diynes. Herein, tethered unconjugated enediynes have been shown to undergo a facile room-temperature RhI-catalysed intramolecular tetradehydro-Diels-Alder reaction to produce highly substituted isobenzofurans, isoindolines and an indane. Furthermore, experimental and computational studies suggest a novel mechanism involving an unprecedented and complex RhI/RhIII/RhI/RhIII redox cycle involving the formation of an unusual strained 7-membered rhodacyclic allene intermediate and a RhIII-stabilized 6-membered ring allene complex.

Investigation of thiazolyl-benzothiophenamides as potential agents for African sleeping sickness.

African sleeping sickness is a potentially fatal neglected disease affecting sub-Saharan Africa. High-throughput screening identified the thiazolyl-benzothiophenamide 1 to be active against the causative parasite, Trypanosoma brucei. This work establishes structure-activity relationships of 1, guiding the design of second generation derivatives. After screening against the clinically relevant species T. b. rhodesiense, the derivative 16 was identified as a suitable candidate for further investigation.

Divergent Pd-catalyzed cross-coupling of allenyloxazolidinones to give chiral 1,3-dienes and vinyloxazolidinones.

The divergent reactivity of 5-allenyloxazolidinones has been explored. This novel building block undergoes Pd(0)-catalyzed cross-coupling with boronic acids to form a wide range of chiral 1,3-dienes and pharmaceutically useful vinyloxazolidinones, the chemoselectivity being tightly controlled by a simple switch in additive.

Divergent gold-catalysed reactions of cyclopropenylmethyl sulfonamides with tethered heteroaromatics.

Cyclopropenylmethyl sulfonamides with tethered heteroaromatics have been demonstrated to undergo divergent gold-catalysed cyclisation reactions. A formal dearomative (4+3) cycloaddition takes place with furan-tethered substrates, yielding densely functionalised 5,7-fused heterocycles related to the bioactive curcusone natural products. Indole-tethered substrates display divergent reactivity giving biologically important tetrahydro-ß-carbolines via a Friedel-Crafts mechanism.