Surmounting Byproduct Inhibition in an Intermolecular Catalytic Asymmetric Alkene Bromoesterification Reaction as Revealed by Kinetic Profiling.

Kinetic profiling has shown that a (DHQD)2PHAL-catalyzed intermolecular asymmetric alkene bromoesterification reaction is inhibited by primary amides, imides, hydantoins, and secondary cyclic amides, which are byproducts of common stoichiometric bromenium ion sources. Two approaches to resolving the inhibition are presented, enabling the (DHQD)2PHAL loading to be dropped from 10 to 1 mol % while maintaining high bromoester conversions in 8 h or less. Iterative post-reaction recrystallizations enabled a homochiral bromonaphthoate ester to be synthesized using only 1 mol % (DHQD)2PHAL.

On the Use of Triarylsilanols as Catalysts for Direct Amidation of Carboxylic Acids.

Triarylsilanols have been reported as the first silicon-centered molecular catalysts for direct amidation of carboxylic acids with amines as identified after a screen of silanols, silanediols, disiloxanediols, and incompletely condensed silsesquioxanes as potential homogeneous catalysts. Subsequent synthesis and testing of various electronically differentiated triarylsilanols have identified tris(p-haloaryl)silanols as more active than the parent triarylsilanol, where the bromide congener is found to be the most active. Catalyst decomposition can be observed by NMR methods, but RPKA methods reveal that product inhibition is operative, where tertiary amides are more inhibitory than secondary amides. Studies using an authentically synthesized triaryl silylester as a putative intermediate in the catalytic system enable a plausible mechanism to be proposed as supported by computationals.

(±)-Polysiphenol and Other Analogues via Symmetrical Intermolecular Dimerizations: A Synthetic, Spectroscopic, Structural, and Computational Study.

We report an improved total synthesis of 4,5-dibromo-9,10-dihydrophenanthrene-2,3,6,7-tetraol, (±)-polysiphenol, via intermolecular McMurray dimerization of 5-bromovanillin and subsequent intramolecular oxidative coupling as the key steps. The synthetic route is applicable to 4,5-dichloro- and 4,5-difluoro-halologues (as well as a 4,5-dialkyl-analogue). Distinctive AA'BB' multiplets in their 1H NMR spectra for the dimethylene bridges of the dibromo and dichloro compounds reveal them to be room-temperature stable atropisomers, while for the difluoro compound they present as a singlet. X-ray crystal structure determinations of their tetramethylated synthetic precursors show atropisomeric twist angles of 48°, 46°, and 32°, respectively, with the former representing the largest yet observed in any 4,5-disubstituted-9,10-dihydrophenanthrene. DFT computational studies reveal an unprecedented two-stage atropisomeric interconversion process involving time-independent asynchronous rotations of the dimethylene bridge and the biaryl axis for halologues containing chlorine or bromine, but a more synchronous rotation for the difluoro analogue.

From Waste to Green Applications: The Use of Recovered Gold and Palladium in Catalysis.

The direct use in catalysis of precious metal recovery products from industrial and consumer waste is a very promising recent area of investigation. It represents a more sustainable, environmentally benign, and profitable way of managing the low abundance of precious metals, as well as encouraging new ways of exploiting their catalytic properties. This review demonstrates the feasibility and sustainability of this innovative approach, inspired by circular economy models, and aims to stimulate further research and industrial processes based on the valorisation of secondary resources of these raw materials. The overview of the use of recovered gold and palladium in catalytic processes will be complemented by critical appraisal of the recovery and reuse approaches that have been proposed.

A Relay Strategy Actuates Pre-Existing Trisubstituted Olefins in Monoterpenoids for Cross-Metathesis with Trisubstituted Alkenes.

A retrosynthetic disconnection-reconnection analysis of epoxypolyenes-substrates that can undergo cyclization to podocarpane-type tricycles-reveals relay-actuated Δ6,7-functionalized monoterpenoid alcohols for ruthenium benzylidene catalyzed olefin cross-metathesis with homoprenyl benzenes. Successful implementation of this approach provided several epoxypolyenes as expected (E/Z, ca. 2-3:1). The method is further generalized for the cross-metathesis of pre-existing trisubstituted olefins in other relay-actuated Δ6,7-functionalized monoterpenoid alcohols with various other trisubstituted alkenes to form new trisubstituted olefins. Epoxypolyene cyclization of an enantiomerically pure, but geometrically impure, epoxypolyene substrate provides an enantiomerically pure, trans-fused, podocarpane-type tricycle (from the E-geometrical isomer).

Epimeric Face-Selective Oxidations and Diastereodivergent Transannular Oxonium Ion Formation Fragmentations: Computational Modeling and Total Syntheses of 12-Epoxyobtusallene IV, 12-Epoxyobtusallene II, Obtusallene X, Marilzabicycloallene C, and Marilzabicycloallene D.

The total syntheses of 12-epoxyobtusallene IV, 12-epoxyobtusallene II, obtusallene X, marilzabicycloallene C, and marilzabicycloallene D as halogenated C15-acetogenin 12-membered bicyclic and tricyclic ether bromoallene-containing marine metabolites from Laurencia species are described. Two enantiomerically pure C4-epimeric dioxabicyclo[8.2.1]tridecenes were synthesized by E-selective ring-closing metathesis where their absolute stereochemistry was previously set via catalytic asymmetric homoallylic epoxidation and elaborated via regioselective epoxide-ring opening and diastereoselective bromoetherification. Epimeric face-selective oxidation of their Δ12,13 olefins followed by bromoallene installation allowed access to the oppositely configured 12,13-epoxides of 12-epoxyobtusallene II and 12-epoxyobtusallene IV. Subsequent exploration of their putative biomimetic oxonium ion formation-fragmentations reactions revealed diastereodivergent pathways giving marilzabicycloallene C and obtusallene X, respectively. The original configurations of the substrates evidently control oxonium ion formation and their subsequent preferred mode of fragmentation by nucleophilic attack at C9 or C12. Quantum modeling of this stereoselectivity at the ωB97X-D/Def2-TZVPPD/SCRF = methanol level revealed that in addition to direction resulting from hydrogen bonding, the dipole moment of the ion-pair transition state is an important factor. Marilzabicycloallene D as a pentahalogenated 12-membered bicyclic ether bromoallene was synthesized by a face-selective chloronium ion initiated oxonium ion formation-fragmentation process followed by subsequent bromoallene installation.

Synthesis, characterisation and reactivity of copper(I) amide complexes and studies on their role in the modified Ullmann amination reaction.

A series of copper(I) alkylamide complexes have been synthesised; copper(I) dicyclohexylamide (1), copper(I) 2,2,6,6-tetramethylpiperidide (2), copper(I) pyrrolidide (3), copper(I) piperidide (4), and copper(I) benzylamide (5). Their solid-state structures and structures in [D6 ]benzene solution are characterised, with the aggregation state in solution determined by a combination of DOSY NMR spectroscopy and DFT calculations. Complexes 1, 2 and 4 are shown to exist as tetramers in the solid state by X-ray crystallography. In [D6 ]benzene solution, complexes 1, 2 and 5 were found by using (1) H DOSY NMR to exist in rapid equilibrium between aggregates with average aggregation numbers of 2.5, 2.4 and 3.3, respectively, at 0.05 M concentration. Conversely, distinct trimeric, tetrameric and pentameric forms of 3 and 4 were distinguishable by one-dimensional (1) H and (1) H DOSY NMR spectroscopy. Complexes 3-5 are found to react stoichiometrically with iodobenzene, in the presence or absence of 1,10-phenanthroline as an ancillary ligand, to give arylamine products indicative of their role as potential intermediates in the modified Ullmann reaction. The role of phenanthroline has also been explored both in the stoichiometric reaction and in the catalytic Ullmann protocol.

Approaches to design non-covalent inhibitors for human granzyme B (hGrB).

A structure-based design campaign for non-covalent small molecule inhibitors of human granzyme B was carried out by means of a virtual screening strategy employing three constraints and probe site-mapping with FTMAP to identify ligand "hot spots". In addition, new scaffolds of diverse structures were subsequently explored with ROCS shape-based superposition methods, following by Glide SP docking, induced fit docking and analysis of QikProp molecular properties. Novel classes of moderately active small molecule blockers (≥25 µM IC50 values) from commercially available libraries were identified, and three novel scaffolds have been synthesized by multi-step procedures. Furthermore, we provide an example of a comprehensive structure-based drug discovery approach to non-covalent inhibitors that relies on the X-ray structure of a covalently bound ligand and suggest that the design path may be compromised by alternative and unknown binding poses.

An enantiospecific polyene cyclization initiated by an enantiomerically pure bromonium ion.

Dimethylaluminum triflate-mediated activation of tetrafluorobenzoates of enantiomerically pure bromohydrins results in enantiospecific polyene cyclizations. The initiation of cyclization by enantiomerically pure bromonium ions and subsequent propagation is not subject to catastrophic erosion of enantiomeric purity by any intramolecular or intermolecular bromonium ion-to-alkene transfer.

A unifying stereochemical analysis for the formation of halogenated C15-acetogenin medium-ring ethers from Laurencia species via intramolecular bromonium ion assisted epoxide ring-opening and experimental corroboration with a model epoxide.

A unifying stereochemical analysis for the formation of the constitutional isomeric halogenated C(15)-acetogenin medium-ring ether natural products from Laurencia species is presented, where an intramolecular bromonium ion assisted epoxide ring-opening reaction of enantiomerically pure epoxides can account for ring-size, the position of the halogen substituents, and relative and absolute configurations of the known natural products. Experimentally, a model epoxide corroborates the feasibility of this process for concurrent formation of 7-, 8- and 9-ring ethers corresponding to the halogenated medium-ring ethers of known metabolites from Laurencia species.

Methyltrimethoxysilane (MTM) as a Reagent for Direct Amidation of Carboxylic Acids.

Methyltrimethoxysilane [MTM, CH3Si(OMe)3] has been demonstrated to be an effective, inexpensive, and safe reagent for the direct amidation of carboxylic acids with amines. Two simple workup procedures that provide the pure amide product without the need for further purification have been developed. The first employs an aqueous base-mediated annihilation of MTM. The second involves simple product crystallization from the reaction mixture providing a low process mass intensity direct amidation protocol.

A stereoselective hydride transfer reaction with contributions from attractive dispersion force control.

The experimentally determined stereochemical outcome of an unprecedented hydride transfer from a lithium alkoxide to an aldehyde is reported, as deconvoluted by the combined use of a single enantiomer alkoxide in conjunction with a deuterium label. The stereoselective outcome is consistent with a computationally predicted transition state model stabilised by contributions from attractive dispersion forces.

Homogeneous Gold Catalysis Using Complexes Recovered from Waste Electronic Equipment.

Despite the greater awareness of elemental sustainability and the benefits of the circular economy concept, much waste electrical and electronic equipment (WEEE) is still destined for landfill. Effective methods for valorizing this waste within our society are therefore imperative. In this contribution, two gold(III) complexes obtained as recovery products from WEEE and their anion metathesis products were investigated as homogenous catalysts. These four recovery products were successfully applied as catalysts for the cyclization of propargylic amides and the condensation of acetylacetone with o-iodoaniline. Impressive activity was also observed in the gold-catalyzed reaction between electron-rich arenes (2-methylfuran, 1,3-dimethoxybenzene, and azulene) and α,ß-unsaturated carbonyl compounds (methyl vinyl ketone and cyclohexenone). These recovered compounds were also shown to be effective catalysts for the oxidative cross-coupling reaction of aryl silanes and arenes. When employed as Lewis acid catalysts for carbonyl-containing substrates, the WEEE-derived gold complexes could also be recovered at the end of the reaction and reused without loss in catalytic activity, enhancing still further the sustainability of the process. This is the first direct application in homogeneous catalysis of gold recovery products sourced from e-waste.

Intramolecular bromonium ion assisted epoxide ring-opening: capture of the oxonium ion with an added external nucleophile.

9-Oxabicyclo[6.1.0]non-4-ene (1) undergoes intramolecular bromonium ion-assisted epoxide ring-opening using N-bromosuccinimide via a presumed oxonium ion that is subject to stereospecific, nonregioselective capture with added external nucleophiles producing novel bicyclo[4.2.1] and bicyclo[3.3.1] ethers. Carboxylic acids (as catalyzed by tetramethylguanidine), alcohols, water, and halides can all function as effective nucleophiles. Stereospecific direct opening of the bromonium ion with carboxylic acids was found to be a competing process where high dilution disfavors this pathway. Halogen-induced isotopic (13)C NMR shifts (Δδ CBr 1.3-1.9 ppb; Δδ CCl 8.6-8.7 ppb) were found to be most useful in unambiguously identifying halogen-bearing carbons, and correlation of these (13)C NMR shifts allowed ready assignment of diastereomeric structures. The structure of adducts 6b, 6c, 7b, 7c, 7d, and 8a-d were all elucidated by X-ray crystallography.

Total synthesis of the marine metabolite (±)-polysiphenol via highly regioselective intramolecular oxidative coupling.

(±)-Polysiphenol (1), an atropisomerically stable 4,5-dibrominated 9,10-dihydrophenanthrene from Polysiphonia ferulacea, was prepared by a biomimetically inspired highly regioselective intramolecular oxidative coupling of a dibrominated dihydrostilbene. The installation of the two bromine atoms prior to oxidative coupling prevents further oxidation to a planar aromatized phenanthrene. By this strategy, the synthesis of (±)-polysiphenol was achieved in four steps in 70% overall yield. Synthesis of the naturally occurring 5,5'-(ethane-1,2-diyl)bis(3-bromobenzene-1,2-diol) (2) (the likely biogenetic precursor of polysiphenol) and 5,5'-(ethane-1,2-diyl)bis(3,4,6-tribromobenzene-1,2-diol) (9) are also reported. The origins of the regioselectivity in the oxidative coupling are explored.

Relay Cross Metathesis for the Iterative Construction of Terpenoids and Synthesis of a Diterpene-Benzoate Macrolide of Biogenetic Relevance to the Bromophycolides.

We report a relay cross metathesis (ReXM) reaction for the construction of terpenoids in an iterative protocol. The protocol features the cross metathesis of a relay-actuated Δ6,7-functionalized C10-monoterpenoid alcohol with C10-monoterpenoid citral to form a C15-sesquiterpene. Subsequent functional group manipulation allows for the method to be repeated in an iterative fashion. The method is used for the synthesis of a diterpene-benzoate macrolide of biogenetic relevance to the bromophycolide family of natural products.

The generation and trapping of enantiopure bromonium ions.

Enantiopure bromonium ions may be generated from enantiopure bromohydrins and derivatives, they can be trapped with an in situ nucleophile to give enantiomerically pure products.

Clarification of the stereochemical course of nucleophilic substitution of arylsulfonate-based nucleophile assisting leaving groups.

Secondary alcohols modified as tosylates, PEG-sulfonates, or quisylates undergo inversion of configuration at the reacting center when treated with lithium halide in acetone at reflux, where the PEG-sulfonates and quisylates are substantially more reactive. In sterically hindered cases, elimination is a competing process. In contrast, when treated with TiCl(4), simple secondary sulfonates give chloride products with partial inversion of configuration. Any observed retention of configuration in a given alkyl sulfonate substrate under these conditions is likely due to neighboring group participation or diastereoselective attack on a carbocation (or ion pair) rather than an S(N)i mechanism.

Bromonium ion induced transannular oxonium ion formation-fragmentation in model obtusallene systems and structural reassignment of obtusallenes V-VII.

Ring-closing metathesis was used to construct the strained 11-membered ring of obtusallenes II (and IV). Bromonium ion induced transannular oxonium ion formation-fragmentation gave the macrocyclic carbon skeleton of obtusallene VII with a bromine atom at C-13, in line with a previously published hypothesis. An additional brominated [5.5.1]bicyclotridecane adduct that must arise from a bromonium ion induced transannular oxonium ion formation-fragmentation could also be isolated, suggesting that this adduct represents the core of an as yet undiscovered natural product. An authentic sample of obtusallene V was studied by NMR spectroscopy, and the position of the halogens at C-7 and C-13 was reassigned on the basis of a (13)C NMR chlorine induced isotopic shift. This revised structure was subsequently confirmed by X-ray crystallography. These findings allow us to confidently conclude that the structures of obtusallenes VII and VI should also be reassigned.

Tetramethyl Orthosilicate (TMOS) as a Reagent for Direct Amidation of Carboxylic Acids.

Tetramethyl orthosilicate (TMOS) is shown to be an effective reagent for direct amidation of aliphatic and aromatic carboxylic acids with amines and anilines. The amide products are obtained in good to quantitative yields in pure form directly after workup without the need for any further purification. A silyl ester as the putative activated intermediate is observed by NMR methods. Amidations on a 1 mol scale are demonstrated with a favorable process mass intensity.