Mechanistic Aspects on [3+2] Cycloaddition (32CA) Reactions of Azides to Nitroolefins: A Computational and Kinetic Study.

[3+2] cycloadditions of nitroolefins have emerged as a selective and catalyst-free alternative for the synthesis of 1,2,3-triazoles from azides. We describe mechanistic studies into the cycloaddition/rearomatization reaction sequence. DFT calculations revealed a rate-limiting cycloaddition step proceeding via an asynchronous TS with high kinetic selectivity for the 1,5-triazole. Kinetic studies reveal a second-order rate law, and 13 C kinetic isotopic effects at natural abundance were measured with a significant normal effect at the conjugated olefinic centers of 1.0158 and 1.0216 at the α and ß-carbons of ß-nitrostyrene. Distortion/interaction-activation strain and energy decomposition analyses revealed that the major regioisomeric pathway benefits from an earlier and less-distorted TS, while intermolecular interaction terms dominate the preference for 1,5- over 1,4-cycloadducts. In addition, the major regioisomer also has more favorable electrostatic and dispersion terms. Additionally, while static DFT calculations suggest a concerted but highly asynchronous Ei-type HNO2 elimination mechanism, quasiclassical direct-dynamics calculations reveal the existence of a dynamic intermediate.

Synthesis of 3-Carbonyl Trisubstituted Furans via Pd-Catalyzed Aerobic Cycloisomerization Reaction: Development and Mechanistic Studies.

Herein, we report the synthesis of 3-carbonyl-trisubstituted furans via Pd-catalyzed oxidative cycloisomerization reactions of 2-alkenyl-1,3-dicarbonyl scaffolds, using molecular oxygen as the sole oxidant to regenerate active palladium catalytic species, featuring good functional tolerance and mild reaction conditions. Deep investigation of intermediates and transition states of the reaction mechanism were conducted via experimental and DFT studies, providing a detailed mechanistical profile. The new developed methodology presents a greener alternative to Wacker-type cycloisomerizations and avoids the use of stoichiometric amounts of oxidants and strong acid additives.

Direct access to tetrasubstituted cyclopentenyl scaffolds through a diastereoselective isocyanide-based multicomponent reaction.

An efficient strategy combining the stereocontrol of organocatalysis with the diversity-generating character of multicomponent reactions is described to produce structurally unique, tetrasubstituted cyclopentenyl frameworks. An asymmetric Michael addition-hemiacetalization between α-cyanoketones and α,ß-unsaturated aliphatic aldehydes was performed for constructing cyclic hemiacetals, which were next employed as chiral bifunctional substrates in a new diastereoselective intramolecular isocyanide-based multicomponent reaction. This approach furnished a diversity of structurally complex compounds - including peptidomimetics and natural product hybrids in high stereoselectivity (up to >99% ee and up to >99 : 1 dr) and in moderate to high yields.

A green metal-free "one-pot" microwave assisted synthesis of 1,4-dihydrochromene triazoles.

The synthesis of several 4-aryl-1,4-dihydrochromene-triazoles was achieved via a metal-free "one-pot" procedure using PEG400 as the sole solvent in an eco-friendly process. Using microwave irradiation, the triazole derivatives were obtained in good yields and short reaction times starting from readily accessible building blocks.

Molecular-level insight in supported olefin metathesis catalysts by combining surface organometallic chemistry, high throughput experimentation, and data analysis.

A combination of high-throughput experimentation (HTE), surface organometallic chemistry (SOMC) and statistical data analysis provided the platform to analyze in situ silica-grafted Mo imido alkylidene catalysts based on a library of 35 phenols. Overall, these tools allowed for the identification of σ-donor electronic effects and dispersive interactions and as key drivers in a prototypical metathesis reaction, homodimerization of 1-nonene. Univariate and multivariate correlation analysis confirmed the categorization of the catalytic data into two groups, depending on the presence of aryl groups in ortho position of the phenol ligand. The initial activity (TOFin) was predominantly correlated to the σ-donor ability of the aryloxy ligands, while the overall catalytic performance (TON1 h) was mainly dependent on attractive dispersive interactions with the used phenol ligands featuring aryl ortho substituents and, in sharp contrast, repulsive dispersive interactions with phenol free of aryl ortho substituents. This work outlines a fast and efficient workflow of gaining molecular-level insight into supported metathesis catalysts and highlights σ-donor ability and noncovalent interactions as crucial properties for designing active d0 supported metathesis catalysts.

Noncovalent Interactions Drive the Efficiency of Molybdenum Imido Alkylidene Catalysts for Olefin Metathesis.

High-throughput experimentation and multivariate modeling allow identification of noncovalent interactions (NCIs) in monoaryloxy-pyrrolide Mo imido alkylidene metathesis catalysts prepared in situ as a key driver for high activity in a representative metathesis reaction (homodimerization of 1-nonene). Statistical univariate and multivariate modeling categorizes catalytic data from 35 phenolic ligands into two groups, depending on the substitution in the ortho position of the phenol ligand. The catalytic activity descriptor TON1h correlates predominantly with attractive NCIs when phenols bear ortho aryl substituents and, conversely, with repulsive NCIs when the phenol has no aryl ortho substituents. Energetic span analysis is deployed to relate the observed NCI and the cycloreversion metathesis step such that aryloxide ligands with no ortho aryls mainly impact the energy of metallacyclobutane intermediates (SP/TBP isomers), whereas aryloxides with pendant ortho aryls influence the transition state energy for the cycloreversion step. While the electronic effects from the aryloxide ligands also play a role, our work outlines how NCIs may be exploited for the design of improved d0 metathesis catalysts.

Diastereoselectivity in the boron aldol reaction of α-alkoxy and α,ß-bis-alkoxy methyl ketones.

In this work, using DFT calculations, we investigated the 1,4 and 1,5 asymmetric induction in boron enolate aldol reactions of α-alkoxy and α,ß-bisalkoxy methyl ketones. We evaluated the steric influence of alkyl substituents at the α position and the stereoelectronic influence of the oxygen protecting groups at the α and ß positions. Theoretical calculations revealed the origins of the 1,4 asymmetric induction in terms of the nature of the ß-substituent. The synergistic effect between the α,ß-syn and α,ß-anti-bisalkoxy stereocenters was elucidated. In the presence of the ß-alkoxy center, the reaction proceeds through the Goodman-Paton 1,5-stereoinduction model, experiencing a minor influence of the α-alkoxy center.

A stereoselective sequential organocascade and multicomponent approach for the preparation of tetrahydropyridines and chimeric derivatives.

A stereoselective multicomponent approach leading to a novel class of pentasubstituted tetrahydropyridines is described. Variation of the components enabled the incorporation of peptide, sugar and steroid moieties to access chimeric derivatives. DFT calculations provide insights about the unprecedented high diastereoselectivity of the MCR.

Cobalt-Catalyzed Stereoselective Synthesis of 2,5- trans-THF Nitrile Derivatives as a Platform for Diversification: Development and Mechanistic Studies.

A straightforward protocol integrating a sustainable approach for the synthesis of new 2,5- trans-THF nitrile derivatives enabling an easy diversification of its side chain scaffolds is described. The reaction tolerated different aromatic and alkyl substituents, affording the corresponding 2,5- trans-THFs in high diastereoselectivity. A detailed mechanistic study using DFT calculation reveals details of the ligand-exchange step, suggesting an inner-sphere syn attack to form the 2,5- trans stereochemistry as the most likely pathway, excluding the previous cation radical intermediate. The formation of a Co-C intermediate is suggested on the basis of the homolytic cleavage to give the previously proposed free carbon radical intermediate.

Organocatalyzed Asymmetric Vinylogous Addition of Oxazole-2(3H)-thiones to α,ß-Unsaturated Ketones: An Additive-Free Approach for Diversification of Heterocyclic Scaffold.

A straightforward organocatalyzed asymmetric addition of oxazole-2(3H)-thiones to α,ß-unsaturated ketones is described. This additive-free Michael reaction in the presence of chiral cinchonine-derived primary amines as catalysts has proven to be highly effective for a wide range of cyclic and acyclic enones, leading to the Michael adducts in very good yields and excellent enantioselectivities. The absolute configuration (R) of compound 5j was unambiguously assigned by X-ray diffraction analysis. Furthermore, experimental and theoretical studies were performed and a mechanism is presented and discussed for this novel reaction.

NIR bacteriochlorin chromophores accessed by Heck and Sonogashira cross-coupling reactions on a tetrabromobacteriochlorin derivative.

The synthesis of a new tetrabromobacteriochlorin BCBr4 is reported having the 3,4-dibromo-1H-pyrrole-2-carbaldehyde (10) as the major precursor. The BCBr4 was successfully employed in Pd cross-coupling reactions with methyl acrylate, phenyl acetylene and 4-ethynylanisole. In all three cases, the desired tetra-coupled products were obtained in good to excellent yields, and present a significant red shift in the UV-Vis bands above 800 nm. DFT and TD-DFT theoretical analyses of the NIR bacteriochlorin chromophores were performed in order to evaluate the effect of ß substitution on their electronic structures.

(1)H chemical shift differences of Prelog-Djerassi lactone derivatives: DFT and NMR conformational studies.

This work reports an experimental and theoretical study of the conformational preferences of several Prelog-Djerassi lactone derivatives, to elucidate the (1)H NMR chemical shift differences in the lactonic core that are associated with the relative stereochemistry of these derivatives. The boat-like conformation of explains the anomalous (1)H chemical shift between H-5a and H-5b, in which the two methyl groups (C-8 and C-9) face H-5b, leading to its higher shielding effect.

An efficient one-pot strategy for the highly regioselective metal-free synthesis of 1,4-disubstituted-1,2,3-triazoles.

A simple and efficient metal-free methodology for the regioselective synthesis of 1,4-disubstituted-1,2,3-triazoles has been developed by applying a novel inverse electron-demand-1,3-dipolar cycloaddition approach. The practical one-pot metal-free strategy can be accomplished with various alkylidene malononitriles and aromatic azides in the presence of base.

Investigation of putative arene-C-H···π(quasi-chelate ring) interactions in copper(I) crystal structures.

Evidence for C-H···π(CuCl···HNCS) interactions, i.e. C-H···π(quasi-chelate ring) where a six-membered quasi-chelate ring is closed by an N-H···Cl hydrogen bond, is presented based on crystal structure analyses of (Ph3P)2Cu[ROC(=S)N(H)Ph]Cl. Similar intramolecular interactions are identified in related literature structures. Calculations suggest that the energy of attraction provided by such interactions approximates 3.5 kcal mol(-1).

Multicomponent combinatorial development and conformational analysis of prolyl peptide-peptoid hybrid catalysts: application in the direct asymmetric Michael addition.

A solution-phase combinatorial approach based on the Ugi four-component reaction was implemented for the development of new prolyl peptide-peptoid hybrid catalysts. Three different elements of diversity were varied during the creation of the set of catalysts: the amine, oxo, and isocyano components. The multicomponent nature of this process enabled the straightforward generation of a series of peptide-peptoid hybrids having the generic sequence Pro-N-R(1)-Xaa-NHR(3), with Xaa being either Gly (R(2) = H) or Aib (R(2) = gem-Me) and R(1) and R(3) either alkyl or amino acid substituents. The catalytic behavior of the peptide-peptoid hybrids was assessed in the asymmetric conjugate addition of aldehydes to nitroolefins, where most of the catalysts showed great efficacy and rendered the Michael adducts with good to excellent enantio- and diastereoselectivity. A molecular modeling study was performed for two distinct catalysts aiming to understand their conformational features. The conformational analysis provided important information for understanding the remarkable stereocontrol achieved during the organocatalytic transformation.

Total synthesis of (-)-goniotrionin.

A stereoselective total synthesis of the reported structure of goniotrionin (4) has been accomplished. The key steps involved the opening of a chiral epoxide, a highly diastereoselective Mukaiyama aerobic oxidative cyclization, a selective 1,2-syn Mukaiyama aldol reaction, and a Noyori reduction.

1,5-Stereoinduction in boron-mediated aldol reactions of ß,δ-bisalkoxy methylketones containing cyclic protecting groups.

A study of the aldol reactions of boron enolates from methylketones that are protected with dimethylacetonide or di-tert-butylsilyl groups and that possess a trans or cis relationship between the chiral centers is presented. The main objective of this work was to evaluate the influence of the relative stereochemistry between the chiral centers and the steric and electronic influences of the cyclic protecting groups on the aldol reactions. The aldol adducts were obtained with moderate to high 1,5-anti stereoselectivity that was dependent on both the identity of the protecting group on the ß,δ-oxygen stereocenters and the relative stereochemistry between the ß and δ chiral centers. A theoretical analysis of the transition states involving these aldol reactions was performed utilizing DFT (density functional theory).

The role of ß-bulky substituents in aldol reactions of boron enolates of methylketones with aldehydes: experimental and theoretical studies by DFT analysis.

In this work, we show the influence of the volume of the ß-substituents on the levels of 1,5-stereoselectivities of aldol reactions of boron enolates generated from ß-alkoxy methylketones with aldehydes. Excellent levels of 1,5-syn stereoinduction were obtained when the ß-protecting group is a silicon ether. This remarkable selectivity is attributed to the volume of the ß-bulky substituent of the corresponding boron enolate. We have investigated a stereochemical model using DFT analysis to rationalize the sense of 1,5-syn stereoselectivities of ß-alkyl-ß-alkoxy methylketones.

Influence of ß-substituents in aldol reactions of boron enolates of ß-alkoxy methylketones.

Moderate to good levels of substrate-based 1,5-syn-stereocontrol could be achieved in the boron-mediated aldol reactions of ß-tert-butyl methylketones with achiral aldehydes, independent of the nature of the ß-alkoxy protecting group (P = PMB or TBS). The analysis of the relative energies of the transition structures by theoretical calculations using the density functional B3LYP shows relative energies favoring the corresponding OUT-1,5-SYN transition structures, explaining the observed 1,5-syn stereoinduction.

Monoamine oxidase inhibitory activities of indolylalkaloid toxins from the venom of the colonial spider Parawixia bistriata: functional characterization of PwTX-I.

Colonial spiders evolved a differential prey-capture behaviour in concert with their venom chemistry, which may be a source of novel drugs. Some highly active tetrahydro-beta-carboline (THbetaC) toxins were recently isolated from the venom of the colonial spider Parawixia bistriata; the spiders use these toxins as part of their chemical arsenal to kill and/or paralyze preys. The major THbetaC compound isolated from this venom was identified as 6-hydroxytrypargine, also known as PwTX-I. Most natural compounds of animal origin occur in low abundance, and the natural abundance of PwTX-I is insufficient for complete functional characterization. Thus, PwTx-I was synthesized using a Pictet-Spengler condensation strategy, and the stereoisomers of the synthetic toxin were separated by chiral chromatography. The fraction of venom containing a mixture of three natural THbetaC toxins and enantiomers of PwTx-I were analyzed for inhibition of monoamine oxidase (MAO)-A and -B and for toxicity to insects. We reveal that the mixture of the natural THbetaC toxins, as well as the enantiomers of PwTx-I, were non-competitive inhibitors of MAO-A and MAO-B and caused potent paralysis of honeybees. The (-)-PwTX-I enantiomer is 2-fold more potent than the (+)-PwTX-I enantiomer in the assays performed.