Organocatalytic Oxidation of Secondary Alcohols Using 1,2-Di(1-naphthyl)-1,2-ethanediamine (NEDA) (Eur. J. Org. Chem. 28/2014)

ChemInform Abstract: Enantioselective Synthesis of 2-Isoxazolines by a One-Flask Conjugate Addition/Oxime-Transfer Process.

Enantioselective isoxazoline synthesis: A combination of 1) a catalytic enantioselective conjugate addition of oximes to alpha,beta-unsaturated aldehydes and 2) an acid-catalyzed intramolecular oxime-transfer reaction lead to the first asymmetric synthesis of 3-unsubstituted 2-isoxazolines (see scheme).

Dual Hydrogen Bond - Enamine Catalysis Enables a Direct Enantioselective Three-Component Domino Reaction

A dual system, composed of an enantioselective enamine catalyst and a multiple-hydrogen-bond catalyst achieves the three-component enantioselective aldehyde—nitroalkene—aldehyde domino reaction using either two similar or two different aldehydes.

ChemInform Abstract: A Catalyst Designed for the Enantioselective Construction of Methyl- and Alkyl-Substituted Tertiary Stereocenters.

Tertiary methyl-substituted stereocenters are present in numerous biologically active natural products. Reported herein is a catalytic enantioselective method for accessing these chiral building blocks using the Mukaiyama-Michael reaction between silyl ketene thioacetals and acrolein. To enable remote enantioface control on the nucleophile, a new iminium catalyst, optimized by three-parameter tuning and by identifying substituent effects on enantioselectivity, was designed. The catalytic process allows rapid access to chiral thioesters, amides, aldehydes, and ketones bearing an α-methyl stereocenter with excellent enantioselectivities, and allowed rapid access to the C4-C13 segment of (-)-b…

Synthesis of 2-isoxazolines: enantioselective and racemic methods based on conjugate additions of oximes.

The formation of 3-unsubstituted 2-isoxazolines by means of condensation reactions between α,β-unsaturated aldehydes and oximes proceeds readily in the presence of catalytic amounts of anilinium salts. Mechanistically, the process involves a fast conjugate addition of the oxime and a slower intramolecular oxime-transfer reaction. The rate of oxime transfer was found to correlate with the acidity of the catalyst. This finding enabled us to discover an enantioselective process in which the fragile conjugate-addition product generated in the first stage is rapidly cyclized into the stable isoxazoline under acidic conditions, with conservation of enantiomeric excess. In summary, herein we descr…

Organocatalytic α-Methylenation of Aldehydes: Preparation of 3,7-Dimethyl-2-Methylene-6-Octenal

4-(Dimethylamino)benzoic acid Pyrrolidine Citronellal 3,7-Dimethyl-2-methylene-6-octenal Formaldehdye, aqueous Keywords: Aldehydes. Methylenation; Organo catalytic reaction; Alpha-substituted acroleins; Intermediates; Rapid synthesis; Functionalities; Waste disposal

Iminium Catalysis (n → π*)

ChemInform Abstract: Dual Hydrogen-Bond/Enamine Catalysis Enables a Direct Enantioselective Three-Component Domino Reaction.

A dual system, composed of an enantioselective enamine catalyst and a multiple-hydrogen-bond catalyst achieves the three-component enantioselective aldehyde—nitroalkene—aldehyde domino reaction using either two similar or two different aldehydes.

Stereocontrol in Diphenylprolinol Silyl Ether Catalyzed Michael Additions : Steric Shielding or Curtin-Hammett Scenario?

The enantioselectivity of amine-catalyzed reactions of aldehydes with electrophiles is often explained by simple steric arguments emphasizing the role of the bulky group of the catalyst that prevents the approach of the electrophile from the more hindered side. This standard steric shielding model has recently been challenged by the discovery of stable downstream intermediates, which appear to be involved in the rate-determining step of the catalytic cycle. The alternative model, referred to as Curtin-Hammett scenario of stereocontrol, assumes that the enantioselectivity is related to the stability and reactivity of downstream intermediates. In our present computational study, we examine th…

Solvent free oxidation of primary alcohols and diols using thymine iron(III) catalyst.

In this study, we developed an efficient and selective iron-based catalyst system for the synthesis of ketones from secondary alcohols and carboxylic acids from primary alcohol. In situ generated iron catalyst of thymine-1-acetate (THA) and FeCl(3) under solvent-free condition exhibits high activity. As an example, 1-octanol and 2-octanol were oxidized to 1-octanoic acid and 2-octanone with 89% and 98% yields respectively.

Palladium-Catalyzed Skeletal Rearrangement of Spirotricyclic Olefins: A Facile One-Pot Strategy for the Synthesis of a Novel Motif with Cyclopentene Fused to Benzofuran and Pyrazolidine

The first utilization of acyclic cyclopropane bearing spirocyclic olefines for the generation of stereospecific complex fused ring systems with an achiral catalyst is reported.

Palladium on Charcoal as a Catalyst for Stoichiometric Chemo- and Stereoselective Hydrosilylations and Hydrogenations with Triethylsilane

Stoichiometric quantities of triethylsilane in the presence of activated Pd/C as the catalyst can be used to effect chemo-, regio-, and stereoselective hydrosilylation and transfer hydrogenation reactions. α,β-Unsaturated aldehydes and ketones are selectively hydrosilylated to give the corresponding enol silanes or transfer hydrogenated to give the saturated carbonyl compounds in the presence of other reducible functional groups.

Base-catalyzed isomerization of 2-isoxazolines enables a two-step enantioselective synthesis of β-hydroxynitriles from enals.

The asymmetric synthesis of β-hydroxynitriles remains a challenge in organic synthesis. Herein we report a convenient synthesis of β-hydroxynitriles from enantiomerically enriched 3-unsubstituted 2-isoxazolines via a base-catalyzed ring-opening reaction that takes place without loss of enantiopurity. In combination with organocatalytic enantioselective synthesis of 3-unsubstituted 2-isoxazolines, the ring-opening enables a short 2-step synthesis of β-hydroxynitriles from α,β-unsaturated aldehydes in high enantiomeric purity.

ChemInform Abstract: Total Synthesis of (+)-Greek Tobacco Lactone.

An enantioselective, protecting-group-free, total synthesis of (+)-Greek tobacco lactone has been achieved by using an organocatalytic Mukaiyama–Michael reaction and a stereospecific oxa-Michael reaction as key steps.

Stereoelectronic Requirements for Optimal Hydrogen-Bond-Catalyzed Enolization

Protein crystallographic analysis of the active sites of enolizing enzymes and structural analysis of hydrogen-bonded carbonyl compounds in small molecule crystal structures, complemented by quantum chemical calculations on related model enolization reactions, suggest a new stereoelectronic model that accounts for the observed out-of-plane orientation of hydrogen-bond donors (HBDs) in the oxyanion holes of enolizing enzymes. The computational results reveal that the lone-pair directionality of HBDs characteristic for hydrogen-bonded carbonyls is reduced upon enolization, and the enolate displays almost no directional preference for hydrogen bonding. Positioning the HBDs perpendicular to the…

Conformational properties and folding analysis of a series of seven oligoamide foldamers

33 crystal structures (11 unsolvated and 22 solvates) of a series of seven oligoamide foldamers were analysed. The crystal structures revealed that despite the structural and environmental differences the series of foldamers prefer only two general conformations, a protohelical @-conformation and a sigmoidal S-conformation. Both conformations also have preferred crystal packing motifs and solvate forming tendencies. Hydrogen bonding was found to be the most decisive factor in conformational preference, but steric properties, the type of the peripheral substituents, as well as solvent and aromatic interactions were also found to have an effect on the conformational details and crystal form. …

Enantioselective Synthesis of 2-Isoxazolines by a One-Flask Conjugate Addition/Oxime-Transfer Process

Enantioselective isoxazoline synthesis: A combination of 1) a catalytic enantioselective conjugate addition of oximes to alpha,beta-unsaturated aldehydes and 2) an acid-catalyzed intramolecular oxime-transfer reaction lead to the first asymmetric synthesis of 3-unsubstituted 2-isoxazolines (see scheme).

Palladium-Catalyzed Dehydrogenative β’-Arylation of β-Keto Esters under Aerobic Conditions: Interplay of Metal and Brønsted Acids

The Bronsted aids: The first dehydrogenative arylation of β-keto esters with arenes under ambient aerobic conditions is described. Under a Pd(II)/Bronsted acid co-catalytic system, regioselective arylations with alkoxylated arenes and phenols were achieved in good yields, even in gram-scale conditions.

Towards Waltheriones C and D: Synthesis of the Oxabicyclic Core

A route to the oxabicyclic cores of the HIV cytoprotective quinolone alkaloids, waltheriones C and D, is described. The approach relies on a stereospecific transannular bromoetherification followed by reductive debromination. The route can also be rendered enantioselective via enzymatic reduction of a key intermediate (>99:1 er).

Mukaiyama–Michael Reactions with trans-2,5-Diarylpyrrolidine Catalysts: Enantioselectivity Arises from Attractive Noncovalent Interactions, Not from Steric Hindrance

The scope of the enantioselective Mukaiyama-Michael reactions catalyzed by trans-2,5-diphenylpyrrolidine has been expanded to include both α- and β-substituted enals. However, the rationalization of the observed enantioselectivity is far from obvious since the catalyst is not very sterically hindered. DFT calculations were carried out to rationalize the observed stereoselectivities. Transition states of the C-C bond formation between iminium intermediates and silyloxyfurans were located and their relative energies were used to estimate the stereoselectivity data. We find excellent agreement between the predicted and observed stereoselectivities. The analysis of intermolecular forces reveals…

An exclusive approach to 3,4-disubstituted cyclopentenes and alkylidene cyclopentenes via the palladium catalyzed ring opening of azabicyclic olefins with aryl halides

A simple and efficient method for the stereoselective ring opening of bicyclic hydrazines with various aryl halides under palladium catalysis has been elaborated. The reactions afforded trans-3,4-disubstituted cyclopentenes or alkylidene cyclopentenes in good to excellent yields. By taking advantage of multiple points of functionalization in the synthesized trans-3-phenyl-4-hydrazino-cyclopentene, we have synthesized the antidepressant Cypenamine (trans-2-phenylcyclopentylamine).

An easy access to fused chromanones via rhodium catalyzed oxidative coupling of salicylaldehydes with heterobicyclic olefins

Abstract Herein we describe a detailed study on the rhodium catalyzed oxidative coupling of salicylaldehydes with heterobicyclic olefins such as diazabicyclic olefins and urea-derived bicyclic olefins. The developed method provides an ideal route to fused chromanone systems in a single synthetic step. Moreover, the scope of this methodology was extended to different oxa/aza-bridged bicyclic urea derivatives.

ChemInform Abstract: Base-Catalyzed Isomerization of 2-Isoxazolines Enables a Two-Step Enantioselective Synthesis of β-Hydroxynitriles from Enals.

Treatment of chiral isoxazoles with catalytic amounts of DBU results in efficient formation of optically active β-hydroxynitriles.

Enzymatic Resolution of 3-oxodicyclopentadiene on a Decagram Scale

The chiral building block 3-oxodicyclopentadiene (1) can be readily resolved on a decagram scale by a short sequence consisting of (1) reduction to the corresponding endo-alcohol, (2) enzymatic oxidative resolution with a ketoreductase enzyme to give (+)-1 and the (+)-form of the endo-alcohol, and (3) reoxidation of the (+)-endo-alcohol with another ketoreductase to give (–)-1. With a selectivity factor of 310, the enantiomeric ratios of the resolved (+)-endo-alcohol and (+)-ketone are both >99:1. Both enzymatic oxidations could be performed with a at least 300:1 substrate/catalyst ratio (w/w).

Cross-Dehydrogenative Couplings between Indoles and beta-Keto Esters: Ligand-Assisted Ligand Tautomerization and Dehydrogenation via a Proton-Assisted Electron Transfer to Pd(II)

Cross-dehydrogenative coupling reactions between β-ketoesters and electron-rich arenes, such as indoles, proceed with high regiochemical fidelity with a range of β-ketoesters and indoles. The mechanism of the reaction between a prototypical β-ketoester, ethyl 2-oxocyclopentanonecarboxylate, and N-methylindole has been studied experimentally by monitoring the temporal course of the reaction by (1)H NMR, kinetic isotope effect studies, and control experiments. DFT calculations have been carried out using a dispersion-corrected range-separated hybrid functional (ωB97X-D) to explore the basic elementary steps of the catalytic cycle. The experimental results indicate that the reaction proceeds v…

Pd/C-Catalyzed Hydrosilylation of Enals and Enones with Triethylsilane: Conformer Populations Control the Stereoselectivity

The palladium-on-charcoal-catalyzed chemo-, regio-, and stereoselective 1,4-hydrosilylation and transfer hydrogenation reactions of α,β-unsaturated aldehydes and ketones with triethylsilane have been investigated with a combination of experimental and theoretical methods. The reaction mechanism has been studied experimentally by monitoring the reactions by 1H NMR from aliquots withdrawn from the stirred reaction mixtures, labeling experiments, and control experiments. Our density functional theory results indicate that both aforementioned reactions are initiated with a dissociative adsorption of the triethylsilane on the palladium catalyst. In the hydrosilylation reaction, the α,β-unsaturat…

(2S,5S)-2-(Bis(4-methoxyphenyl)((trimethylsilyl)oxy)methyl)-5-(4-methoxy-3,5-dimethylphenyl)pyrrolidine

Carboxylate catalyzed isomerization of β,γ‐unsaturated N-acetylcysteamine thioesters

We demonstrate herein the capacity of simple carboxylate salts – tetrametylammonium and tetramethylguanidinium pivalate – to act as catalysts in the isomerization of β,γ-unsaturated thioesters to α,β-unsaturated thioesters. The carboxylate catalysts gave reaction rates comparable to those obtained with DBU, but with fewer side reactions. The reaction exhibits a normal secondary kinetic isotope effect ( k 1H / k 1D = 1.065±0.026) with a β,γ−deuterated substrate. Computational analysis of the mechanism provides a similar value ( k 1H / k 1D = 1.05) with a mechanism where γ-reprotonation of the enolate intermediate is rate determining. peerReviewed

Rhodium catalyzed oxidative coupling of salicylaldehydes with diazabicyclic olefins: a one pot strategy involving aldehyde C–H cleavage and π-allyl chemistry towards the synthesis of fused ring chromanones

An efficient one pot strategy for the synthesis of cyclopentene fused chromanone derivatives through the direct oxidative coupling of salicylaldehydes with bicyclic olefins in the presence of a rhodium-copper catalyst system is described. This is the first report on the ring opening-ring closing of bicyclic hydrazines via metal catalyzed oxidative coupling reaction.

Total Synthesis of (+)-Greek Tobacco Lactone

An enantioselective, protecting-group-free, total synthesis of (+)-Greek tobacco lactone has been achieved by using an organocatalytic Mukaiyama–Michael reaction and a stereospecific oxa-Michael reaction as key steps.

ChemInform Abstract: Synthesis of 2-Isoxazolines: Enantioselective and Racemic Methods Based on Conjugate Additions of Oximes.

Acidic anilinium salts catalyze the direct formation of racemic 2-isoxazolines from enals and oximes by means of consecutive oxime conjugate-addition and intramolecular oxime-transfer reaction.

Organocatalytic Oxidation of Secondary Alcohols Using 1,2-Di(1-naphthyl)-1,2-ethanediamine (NEDA)

Diamine, 1,2-di(1-naphthyl)-1,2-ethanediamine (NEDA), efficiently catalyzes the oxidation of alcohols by using TBHP as an oxidant. Notably, secondary benzyl alcohols are oxidized in almost quantitative yields, and the catalyst also displays high activity towards even hindered cycloaliphatic secondary alcohols. With enantiopure (R,R)-NEDA, oxidative kinetic resolution can be realized and depending on the alcohol ee up to 99 % are achieved.

ChemInform Abstract: Rhodium(III)-Catalyzed Ring-Opening of Strained Olefins Through C-H Activation of O-Acetyl Ketoximes: An Efficient Synthesis of trans-Functionalized Cyclopentenes and Spiro[2.4]heptenes.

An efficient strategy for the stereoselective synthesis of functionalized cyclopentenes and spiro[2.4]heptenes from strained olefins via C–H activation of aryl ketone O-acetyl ketoximes using [RhCl2Cp∗]2 catalyst is described. The results revealed that a wide range of readily accessible aryl and heteroaryl ketoximes are compatible in this method for the ring opening of bicyclic and spirotricyclic olefins.

ChemInform Abstract: Cross-Dehydrogenative Couplings Between Indoles and β-Keto Esters: Ligand-Assisted Ligand Tautomerization and Dehydrogenation via a Proton-Assisted Electron Transfer to Pd(II).

Cross-dehydrogenative coupling reactions between β-ketoesters and electron-rich arenes, such as indoles, proceed with high regiochemical fidelity with a range of β-ketoesters and indoles. The mechanism of the reaction between a prototypical β-ketoester, ethyl 2-oxocyclopentanonecarboxylate, and N-methylindole has been studied experimentally by monitoring the temporal course of the reaction by (1)H NMR, kinetic isotope effect studies, and control experiments. DFT calculations have been carried out using a dispersion-corrected range-separated hybrid functional (ωB97X-D) to explore the basic elementary steps of the catalytic cycle. The experimental results indicate that the reaction proceeds v…

ChemInform Abstract: Mukaiyama-Michael Reactions with trans-2,5-Diarylpyrrolidine Catalysts: Enantioselectivity Arises from Attractive Noncovalent Interactions, Not from Steric Hindrance.

The 2,5-diphenylpyrrolidine-catalyzed enantioselective Mukaiyama—Michael reaction between substituted furans and enals is studied.

Enantioselective Mannich reaction of β-keto esters with aromatic and aliphatic imines using a cooperatively assisted bifunctional catalyst

An efficient urea-enhanced thiourea catalyst enables the enantioselective Mannich reaction between β-keto esters and N-Boc-protected imines under mild conditions and minimal catalyst loading (1–3 mol %). Aliphatic and aromatic substituents are tolerated on both reaction partners, affording the products in good enantiomeric purity. The corresponding β-amino ketones can readily be accessed via decarboxylation without loss of enantiomeric purity.

Bifunctional Acid-Base Catalysis

Acid-base catalysis with bifunctional catalysts is a very prominent catalytic strategy in both small-molecule organocatalysts as well as enzyme catalysis. In both worlds, small-molecule catalysts and enzymatic catalysis, a variety of different general acids or hydrogen bond donors are used. In this chapter, important parallels between small molecule catalysts and enzymes are discussed, and a comparison is also made to the emerging field of frustrated Lewis pair catalysis.

Dihydrooxazine Oxides as Key Intermediates in Organocatalytic Michael Additions of Aldehydes to Nitroalkenes

Pause and play: dihydrooxazine oxides are stable intermediates that are protonated directly, without the intermediacy of the zwitterions, in organocatalytic Michael additions of aldehydes and nitroalkenes (see scheme, R=alkyl). Protonation of these species explains both the role of the acid co-catalyst in these reactions, and the observed stereochemistry when the reaction is conducted with α-alkylnitroalkenes.

Stereoselective Hydrosilylation of Enals and Enones Catalysed by Palladium Nanoparticles

A highly versatile and efficient hydrosilylation method by palladium nanoparticle catalysis allows the direct and chemoselective synthesis of 1) enolsilanes of high isomeric purity, 2) saturated aldehydes or ketones, or 3) the corresponding saturated acetals from α,β-unsaturated aldehydes or ketones. The choice of the product is determined by simply switching the solvent from THF to mixtures of THF/water or THF/alcohol.

Palladium-catalyzed dehydrogenative β'-functionalization of β-keto esters with indoles at room temperature.

The dehydrogenative β′-functionalization of α-substituted β-keto esters with indoles proceeds with high regioselectivities (C3-selective for the indole partner and β′-selective for the β-keto ester) and good yields under mild palladium catalysis at room temperature with a variety of oxidants. Two possible mechanisms involving either late or early involvement of indole are presented.

A Catalyst Designed for the Enantioselective Construction of Methyl- and Alkyl-Substituted Tertiary Stereocenters

Tertiary methyl-substituted stereocenters are present in numerous biologically active natural products. Reported herein is a catalytic enantioselective method for accessing these chiral building blocks using the Mukaiyama-Michael reaction between silyl ketene thioacetals and acrolein. To enable remote enantioface control on the nucleophile, a new iminium catalyst, optimized by three-parameter tuning and by identifying substituent effects on enantioselectivity, was designed. The catalytic process allows rapid access to chiral thioesters, amides, aldehydes, and ketones bearing an α-methyl stereocenter with excellent enantioselectivities, and allowed rapid access to the C4-C13 segment of (-)-b…

Organocatalysts Fold to Generate an Active Site Pocket for the Mannich Reaction

Catalysts containing urea, thiourea and tertiary amine groups fold into a three-dimensional organized structure in solution both in the absence as well as in the presence of substrates or substrate analogues, as indicated by solution NMR and computational studies. These foldamer catalysts promote Mannich reactions with both aliphatic and aromatic imines and malonate esters. Hammett plot and secondary kinetic isotope effects provide evidence for the C-C bond forming event as the turnoverlimiting step of the Mannich reaction. Computational studies suggest two viable pathways for the C-C bond formation step, differing in the activation modes of the malonate and imine substrates. The results sh…

Photoactive Yellow Protein Chromophore Photoisomerizes around a Single Bond if the Double Bond Is Locked

Photoactivation in the Photoactive Yellow Protein, a bacterial blue light photoreceptor, proceeds via photo-isomerization of the double C=C bond in the covalently attached chromophore. Quantum chemistry calculations, however, have suggested that in addition to double bond photo-isomerization, the isolated chromophore and many of its analogues, can isomerize around a single C-C bond as well. Whereas double bond photo-isomerization has been observed with x-ray crystallography, experimental evidence for single bond photo-isomerization is currently lacking. Therefore, we have synthesized a chromophore analogue, in which the formal double bond is covalently locked in a cyclopentenone ring and ca…

ChemInform Abstract: Palladium-Catalyzed Skeletal Rearrangement of Spirotricyclic Olefins: A Facile One-Pot Strategy for the Synthesis of a Novel Motif with Cyclopentene Fused to Benzofuran and Pyrazolidine.

The first utilization of acyclic cyclopropane bearing spirocyclic olefines for the generation of stereospecific complex fused ring systems with an achiral catalyst is reported.

Rhodium(III)-catalyzed ring-opening of strained olefins through C–H activation of O-acetyl ketoximes: an efficient synthesis of trans-functionalized cyclopentenes and spiro[2.4]heptenes

An efficient strategy for the stereoselective synthesis of functionalized cyclopentenes and spiro[2.4]heptenes from strained olefins via C–H activation of aryl ketone O-acetyl ketoximes using [RhCl2Cp∗]2 catalyst is described. The results revealed that a wide range of readily accessible aryl and heteroaryl ketoximes are compatible in this method for the ring opening of bicyclic and spirotricyclic olefins.

ChemInform Abstract: Rhodium Catalyzed Oxidative Coupling of Salicylaldehydes with Diazabicyclic Olefins: A One-Pot Strategy Involving Aldehyde C-H Cleavage and π-Allyl Chemistry Towards the Synthesis of Fused Ring Chromanones.

The title reaction involves the first example of ring opening and ring closing of bicyclic hydrazines (I) via metal catalyzed oxidative coupling reaction.

Folding Patterns in a Family of Oligoamide Foldamers

A series of small, unsymmetrical pyridine-2,6-dicarboxylamide oligoamide foldamers with varying lengths and substituents at the end groups were synthetized to study their conformational properties and folding patterns. The @-type folding pattern resembled the oxyanion-hole motifs of enzymes, but several alternative folding patterns could also be characterized. Computational studies revealed several alternative conformers of nearly equal stability. These folding patterns differed from each other in their intramolecular hydrogen-bonding patterns and aryl-aryl interactions. In the solid state, the foldamers adopted either the globular @-type fold or the more extended S-type conformers, which w…

ChemInform Abstract: Dihydrooxazine Oxides as Key Intermediates in Organocatalytic Michael Additions of Aldehydes to Nitroalkenes.

Pause and play: dihydrooxazine oxides are stable intermediates that are protonated directly, without the intermediacy of the zwitterions, in organocatalytic Michael additions of aldehydes and nitroalkenes (see scheme, R=alkyl). Protonation of these species explains both the role of the acid co-catalyst in these reactions, and the observed stereochemistry when the reaction is conducted with α-alkylnitroalkenes.

Total Synthesis of Stemoamide, 9a-epi-Stemoamide, and 9a,10-epi-Stemoamide: Divergent Stereochemistry of the Final Methylation Steps

Total syntheses of stemoamide, 9a-epi-stemoamide, and 9a,10-epi-stemoamide by a convergent A + B ring-forming strategy is reported. The synthesis required a diastereoselective late-stage methylation of the ABC stemoamide core that successfully enabled access to three of the four possible diastereomeric structures. For the natural stemoamide series, the diastereoselectivity can be rationalized both by kinetic and thermodynamic arguments, whereas for the natural 9a-epi-stemoamide series, the kinetic selectivity is explained by the prepyramidalization of the relevant enolate.

Conformationally Locked Pyramidality Explains the Diastereoselectivity in the Methylation of trans-Fused Butyrolactones

A stereoselectivity model inspired by the total synthesis of stemona alkaloids is developed to explain why enolate-derived 3,4-fused butyrolactones are methylated with a preference for syn alkylation. The model shows how conformational locking present in nonplanar enolate structures favors syn over anti methylation, due to less significant structural distortions in the syn pathway. The developed model was also successfully used to rationalize selectivities of previously documented methylation reactions. peerReviewed

High resolution crystal structures of triosephosphate isomerase complexed with its suicide inhibitors: The conformational flexibility of the catalytic glutamate in its closed, liganded active site

The key residue of the active site of triosephosphate isomerase (TIM) is the catalytic glutamate, which is proposed to be important (i) as a catalytic base, for initiating the reaction, as well as (ii) for the subsequent proton shuttling steps. The structural properties of this glutamate in the liganded complex have been investigated by studying the high resolution crystal structures of typanosomal TIM, complexed with three suicide inhibitors: (S)-glycidol phosphate ((S)-GOP, at 0.99 A resolution), (R)-glycidol phosphate, ((R)-GOP, at 1.08 A resolution), and bromohydroxyacetone phosphate (BHAP, at 1.97 A resolution). The structures show that in the (S)-GOP active site this catalytic glutama…

ChemInform Abstract: An Easy Access to Fused Chromanones via Rhodium Catalyzed Oxidative Coupling of Salicylaldehydes with Heterobicyclic Olefins.

Diazabicyclic and urea-derived bicyclic olefins react with salicylaldehydes to produce various types of fused chromanone systems of biological interest in a single step (mechanism).

A Three-Component Palladium-Catalyzed Oxidative CC Coupling Reaction: A Domino Process in Two Dimensions

Reaction Mechanism of an Intramolecular Oxime Transfer Reaction: A Computational Study

Density functional theory (PBE0/def2-TZVPP) calculations in conjunction with a polarizable continuum model were used to assess the mechanism of the intramolecular oxime transfer reaction that leads to the formation of isoxazolines. Different diastereomers of the intermediates as well as different oximes (formaldehyde and acetone oxime) were considered. The computed reaction profile predicts the water-addition and -expulsion steps as the highest barriers along the pathway, a conclusion that is in line with the experimental evidence obtained previously for these reactions.

First Principles Calculations for Hydrogenation of Acrolein on Pd and Pt: Chemoselectivity Depends on Steric Effects on the Surface

The chemoselective hydrogenation of acrolein on Pt(111) and Pd(111) surfaces is investigated employing density functional theory calculations. The computed potential energy surfaces together with the analysis of reaction mechanisms demonstrate that steric effects are an important factor that governs chemoselectivity. The reactions at the C=O functionality require more space than the reactions at the C=C functionality. Therefore the formation of allyl alcohol is more favorable at low coverage, while the reduction of the C=C bond and the formation of propanal becomes kinetically more favorable at higher coverage. The elementary reaction steps are found to follow different reaction mechanisms,…

Oxyanion Holes and Their Mimics

A Highly Enantioselective Access to Tetrahydroisoquinoline and β-Carboline Alkaloids with Simple Noyori-Type Catalysts in Aqueous Media

Cooperative Assistance in Bifunctional Organocatalysis: Enantioselective Mannich Reactions with Aliphatic and Aromatic Imines

both of which contain a thiourea moiety (Scheme 1).The catalysts are capable of deprotonating suitable nucleo-philes, such as activated carbonyl compounds. This proton-transfer reaction generates an ion pair, which is composed ofthe protonated catalyst and the anionic nucleophile interact-ing through hydrogen bonds. At least one of the NH moietiesin the protonated catalyst is involved in activating theelectrophilic reaction partner.

ChemInform Abstract: Cooperative Assistance in Bifunctional Organocatalysis: Enantioselective Mannich Reactions with Aliphatic and Aromatic Imines.

both of which contain a thiourea moiety (Scheme 1).The catalysts are capable of deprotonating suitable nucleo-philes, such as activated carbonyl compounds. This proton-transfer reaction generates an ion pair, which is composed ofthe protonated catalyst and the anionic nucleophile interact-ing through hydrogen bonds. At least one of the NH moietiesin the protonated catalyst is involved in activating theelectrophilic reaction partner.

Mukaiyama–Michael Reactions with Acrolein and Methacrolein: A Catalytic Enantioselective Synthesis of the C17–C28 Fragment of Pectenotoxins

Enantioselective iminium-catalyzed reactions with acrolein and methacrolein are rare. A catalytic enantioselective Mukaiyama-Michael reaction that readily accepts acrolein or methacrolein as substrates, affording the products in good yields and 91-97% ee, is presented. As an application of the methodology, an enantioselective route to the key C17-C28 segment of the pectenotoxin using the Mukaiyama-Michael reaction as the key step is described.

ChemInform Abstract: Palladium-Catalyzed Dehydrogenative β′-Functionalization of β-Keto Esters with Indoles at Room Temperature.

The dehydrogenative β′-functionalization of α-substituted β-keto esters with indoles proceeds with high regioselectivities (C3-selective for the indole partner and β′-selective for the β-keto ester) and good yields under mild palladium catalysis at room temperature with a variety of oxidants. Two possible mechanisms involving either late or early involvement of indole are presented.

Dynamic Refolding of Ion-Pair Catalysts in Response to Different Anions.

Four distinct folding patterns were identified in two foldamer-type urea-thiourea catalysts bearing a basic dimethylamino unit by a combination of X-ray crystallography, solution NMR studies, and computational studies (DFT). These patterns are characterized by different intramolecular hydrogen bonding schemes that arise largely from different thiourea conformers. The free base forms of the catalysts are characterized by folds where the intramolecular hydrogen bonds between the urea and the thiourea units remain intact. In contrast, the catalytically relevant salt forms of the catalyst, where the catalyst forms an ion pair with the substrate or substrate analogues, appear in two entirely dif…

Synthetic Studies towards Pectenotoxin-2: Synthesis of the Nonanomeric 10-epi-ABCDE Ring Segment by Kinetic Spiroketalization

The synthesis of the nonanomeric 10-epi-ABCDE ring system of pectenotoxin-2 has been achieved by using a kinetic spiroketalization reaction. The synthesis of the spiroketalization precursor was achieved through a cross-metathesis/hydro-genation sequence. The formation of the epi-C10 isomer resulted from an unexpected anti-Felkin selective addition of organometallic nucleophiles to the advanced CDE ring precursor. This addition reaction was investigated with differently protected α,β-dioxygenated model aldehydes, which displayed similar anti-Felkin selectivities with organometallic nucleophiles.

ChemInform Abstract: Enantioselective Mannich Reaction of β-Keto Esters with Aromatic and Aliphatic Imines Using a Cooperatively Assisted Bifunctional Catalyst.

The title reaction tolerates aliphatic and aromatic substituents on both reaction partners, affording products (III) as a mixture of inseparable diastereomers with low or without any diastereoselectivity.

Structures of yeast peroxisomal Δ(3),Δ(2)-enoyl-CoA isomerase complexed with acyl-CoA substrate analogues: the importance of hydrogen-bond networks for the reactivity of the catalytic base and the oxyanion hole.

Δ3,Δ2-Enoyl-CoA isomerases (ECIs) catalyze the shift of a double bond from 3Z- or 3E-enoyl-CoA to 2E-enoyl-CoA. ECIs are members of the crotonase superfamily. The crotonase framework is used by many enzymes to catalyze a wide range of reactions on acyl-CoA thioesters. The thioester O atom is bound in a conserved oxyanion hole. Here, the mode of binding of acyl-CoA substrate analogues to peroxisomalSaccharomyces cerevisiaeECI (ScECI2) is described. The best defined part of the bound acyl-CoA molecules is the 3′,5′-diphosphate-adenosine moiety, which interacts with residues of loop 1 and loop 2, whereas the pantetheine part is the least well defined. The catalytic base, Glu158, is hydrogen-bo…

Catalytic Enantioselective Total Synthesis of (+)-Lycoperdic Acid.

A concise enantio- and stereocontrolled synthesis of (+)-lycoperdic acid is presented. The stereochemical control is based on iminium-catalyzed Mukaiyama–Michael reaction and enamine-catalyzed organocatalytic α-chlorination steps. The amino group was introduced by azide displacement, affording the final stereochemistry of (+)-lycoperdic acid. Penultimate hydrogenation and hydrolysis afforded pure (+)-lycoperdic acid in seven steps from a known silyloxyfuran. peerReviewed

Synthesis of Trisaccharides by Hetero-Diels–Alder Welding of Two Monosaccharide Units

A new strategy for the synthesis of di- and trisaccharides based on the de novo synthesis of the linking saccharide unit is presented. In this strategy, functionalized monosaccharide building blocks already incorporating the glycosidic linkages are welded together using a metal-catalyzed hetero-Diels–Alder (HDA) reaction to generate a new monosaccharide unit between them. The highest yields and selectivities in the HDA reaction were obtained by using chiral Schiff base chromium complexes. Disaccharide products were accessible by reaction of Danishefsky's diene with acetyl- and benzyl-protected galactoside aldehydes. For the synthesis of trisaccharide products, acetyl-protected glucose or ga…

CCDC 1901894: Experimental Crystal Structure Determination

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CCDC 1436660: Experimental Crystal Structure Determination

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CCDC 1973338: Experimental Crystal Structure Determination

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CCDC 1436663: Experimental Crystal Structure Determination

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CCDC 1438546: Experimental Crystal Structure Determination

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CCDC 1038219: Experimental Crystal Structure Determination

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CCDC 1038222: Experimental Crystal Structure Determination

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CCDC 1827648: Experimental Crystal Structure Determination

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CCDC 952087: Experimental Crystal Structure Determination

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CCDC 1038221: Experimental Crystal Structure Determination

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CCDC 1436674: Experimental Crystal Structure Determination

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CCDC 1831369: Experimental Crystal Structure Determination

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CCDC 1901892: Experimental Crystal Structure Determination

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CCDC 1556565: Experimental Crystal Structure Determination

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CCDC 1436667: Experimental Crystal Structure Determination

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CCDC 1436665: Experimental Crystal Structure Determination

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CCDC 1449575: Experimental Crystal Structure Determination

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CCDC 917055: Experimental Crystal Structure Determination

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CCDC 1436670: Experimental Crystal Structure Determination

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CCDC 1972521: Experimental Crystal Structure Determination

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CCDC 1038220: Experimental Crystal Structure Determination

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CCDC 1003178: Experimental Crystal Structure Determination

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CCDC 1038217: Experimental Crystal Structure Determination

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CCDC 997889: Experimental Crystal Structure Determination

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CCDC 1901895: Experimental Crystal Structure Determination

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CCDC 1436669: Experimental Crystal Structure Determination

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CCDC 1436668: Experimental Crystal Structure Determination

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CCDC 1003179: Experimental Crystal Structure Determination

Related Article: Mikko V. Leskinen , Ádám Madarász , Kai-Tai Yip , Aini Vuorinen , Imre Pápai , Antti J. Neuvonen , and Petri M. Pihko|2014|J.Am.Chem.Soc.|136|6453|doi:10.1021/ja501681y

CCDC 1436662: Experimental Crystal Structure Determination

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CCDC 1901899: Experimental Crystal Structure Determination

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CCDC 1901897: Experimental Crystal Structure Determination

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CCDC 1901898: Experimental Crystal Structure Determination

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CCDC 1973339: Experimental Crystal Structure Determination

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CCDC 1436673: Experimental Crystal Structure Determination

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CCDC 1038216: Experimental Crystal Structure Determination

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CCDC 1038223: Experimental Crystal Structure Determination

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CCDC 1436659: Experimental Crystal Structure Determination

Related Article: Aku Suhonen, Minna Kortelainen, Elisa Nauha, Sanna Yliniemelä-Sipari, Petri M. Pihko, Maija Nissinen|2016|CrystEngComm|18|2005|doi:10.1039/C5CE02458G

CCDC 1827649: Experimental Crystal Structure Determination

Related Article: Katja Kärki, Juha H. Siitonen, Mona Cederström, Sami Kortet, Petri M. Pihko|2018|Synlett|29|1723|doi:10.1055/s-0037-1610109

CCDC 1436672: Experimental Crystal Structure Determination

Related Article: Aku Suhonen, Minna Kortelainen, Elisa Nauha, Sanna Yliniemelä-Sipari, Petri M. Pihko, Maija Nissinen|2016|CrystEngComm|18|2005|doi:10.1039/C5CE02458G

CCDC 1436666: Experimental Crystal Structure Determination

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CCDC 1038215: Experimental Crystal Structure Determination

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CCDC 1038218: Experimental Crystal Structure Determination

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CCDC 1436664: Experimental Crystal Structure Determination

Related Article: Aku Suhonen, Minna Kortelainen, Elisa Nauha, Sanna Yliniemelä-Sipari, Petri M. Pihko, Maija Nissinen|2016|CrystEngComm|18|2005|doi:10.1039/C5CE02458G

CCDC 1901893: Experimental Crystal Structure Determination

Related Article: Antti J. Neuvonen, Dimitris Noutsias, Filip Topić, Kari Rissanen, Tamás Földes, Imre Pápai, Petri M. Pihko|2019|J.Org.Chem.|84|15009|doi:10.1021/acs.joc.9b01980

CCDC 1436671: Experimental Crystal Structure Determination

Related Article: Aku Suhonen, Minna Kortelainen, Elisa Nauha, Sanna Yliniemelä-Sipari, Petri M. Pihko, Maija Nissinen|2016|CrystEngComm|18|2005|doi:10.1039/C5CE02458G

CCDC 1901896: Experimental Crystal Structure Determination

Related Article: Antti J. Neuvonen, Dimitris Noutsias, Filip Topić, Kari Rissanen, Tamás Földes, Imre Pápai, Petri M. Pihko|2019|J.Org.Chem.|84|15009|doi:10.1021/acs.joc.9b01980

CCDC 1436661: Experimental Crystal Structure Determination

Related Article: Aku Suhonen, Minna Kortelainen, Elisa Nauha, Sanna Yliniemelä-Sipari, Petri M. Pihko, Maija Nissinen|2016|CrystEngComm|18|2005|doi:10.1039/C5CE02458G

CCDC 782677: Experimental Crystal Structure Determination

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CCDC 1827647: Experimental Crystal Structure Determination

Related Article: Katja Kärki, Juha H. Siitonen, Mona Cederström, Sami Kortet, Petri M. Pihko|2018|Synlett|29|1723|doi:10.1055/s-0037-1610109