Stereoselective Outcome Research Articles

Synthesis of Mono‐ and Bis‐Thiourea Organocatalysts and Their Application in Stereoselective Glycosylation Reactions

AbstractTwo new mono‐thiourea, four bis‐thiourea and one squaramide organocatalysts were synthesised from L‐tartaric acid. These organocatalysts were able to activate glycosyl phosphates for stereoselective nucleophilic substitution reactions with broad functional group compatibility under mild conditions. The influence of the number and position of the thiourea groups and the proximity of the asymmetric centre to the catalytic important atoms for the stereoselective outcome of the glycosylation reactions was studied. 1,2‐cis Glycosides were obtained in up to 85 % yield and high diastereoselectivity (up to α:β 83 : 17).

Mechanistic insight into benzylidene-directed glycosylation reactions using cryogenic infrared spectroscopy

The stereoselective formation of 1,2-cis glycosidic linkages is challenging. The currently most widely used strategy for their installation uses 4,6-O-benzylidene-protected building blocks. The stereoselectivity of this reaction is thought to be driven by a covalent intermediate, which reacts via an SN2 mechanism. However, the role of cationic SN1-type intermediates in this reaction is unclear. Here we elucidate the structure of glycosyl cations carrying 4,6-O-benzylidene groups using cryogenic infrared ion spectroscopy and computational methods. The data reveal that the intermediates form anhydro cations, which correlates well with the stereoselective outcome of SN1-type glycosylations. The study highlights how cryogenic infrared spectroscopy can elucidate the role of intermediates in sugar chemistry and how these structural data can be linked to reactions in solution.

Asymmetric and Chemoselective Iridium Catalyzed Hydrogenation of Conjugated Unsaturated Oxime Ethers.

Research on the chemoselective metal-catalyzed hydrogenation of conjugated π-systems has mostly been focussed on enones. Herein, we communicate the understudied asymmetric hydrogenation of enimines catalyzed by N,P-iridium complexes and chemoselective toward the alkene. A number of enoxime ethers underwent hydrogenation smoothly to yield the desired products in high yield and stereopurity (up to 99 % yield, up to 99 % ee). No hydrogenation of the C=N π-bond was observed under the applied reaction conditions (20 bar H2, rt, DCM). It was demonstrated that the chiral oxime ether could be hydrolyzed into the ketone with complete preservation of the installed stereogenity at the α-carbon. At last, a binding mode of the substrate to the active iridium catalyst and the consequence for the stereoselective outcome was proposed.

Selectivity in Catalytic Asymmetric Formal [3 + 3] Annulation of 2-Enoyl-pyridine N-Oxide with Benzyl Methyl Ketone

The asymmetric formal [3 + 3] annulation process of (E)-2-(3-phenylacryloyl)pyridine N-oxide with benzyl methyl ketone was investigated. The possibility of a stereoselective outcome was checked using salts of natural amino acids, as well as chiral bifunctional derivatives containing amino groups and thiourea or squaramide fragments as organocatalysts. Different types of organocatalysts applied led to opposite enantiomers of 2-(3-oxo-4,5-diphenyl-cyclohex-1-en-yl)pyridine 1-oxide (up to 60% ee). Spectroscopic analysis of the isolated product and analysis of the reaction course was carried out, taking into account the obtained regio- and stereoselectivity. In order to verify the postulated results, calculations of the energy of the intermediate reaction products and the final product using the Kohn–Sham Density Functional Theory (KS-DFT) were made.

Non-covalent interactions in the diastereoselective synthesis of cis-2,3-dihydrobenzofurans: experimental and computational studies.

The diastereoselective synthesis of 2,3-DHBs has been previously reported via an intramolecular Michael addition reaction using alkali bases such as Cs2CO3 and K2CO3. However, no systematic study has been performed to understand the possible role of bases in the mechanism of the reaction and factors behind the stereoselective outcome of the reaction. Herein, from experimental and theoretical points of view, we disclose the role of the cesium salt in the rate-determining step along the catalytic cycle and the key role of stabilizing non-covalent interactions in the stereoselective outcome of the reaction.

On the influence of solvent on the stereoselectivity of glycosylation reactions

Methodology development in carbohydrate chemistry entails the stereoselective formation of C–O bonds as a key step in the synthesis of oligo- and polysaccharides. The anomeric selectivity of a glycosylation reaction is affected by a multitude of parameters, such as the nature of the donor and acceptor, activator/promotor system, temperature and solvent. The influence of different solvents on the stereoselective outcome of glycosylation reactions employing thioglucopyranosides as glycosyl donors with a non-participating protecting group at position 2 has been studied. A large change in selectivity as a function of solvent was observed and a correlation between selectivity and the Kamlet-Taft solvent parameter π* was found. Furthermore, molecular modeling using density functional theory methodology was conducted to decipher the role of the solvent and possible reaction pathways were investigated.

Enantioselective Nickel-Catalyzed Si–C(sp2) Bond Activation and Migratory Insertion to Aldehydes: Reaction Scope and Mechanism

Transition-metal-catalyzed silicon–carbon bond activation is one of the most important processes in both organosilicon chemistry and homogeneous catalysis that is still rarely reported in the past decades, and the enantioselective versions based on transition-metal-catalyzed Si–C bond activation remain an ongoing challenge in asymmetric catalysis. Herein, we report a convenient and enantioselective Si–C bond cleavage-initiated [4 + 2] annulation of benzosilacyclobutenes with aldehydes, which provides an access to the direct synthesis of chiral six-membered oxasilacycles and their derivatives with high yields and enantioselectivities (up to 97% ee). The catalytic asymmetric reaction proceeds smoothly with the aid of a chiral TADDOL-derived phosphoramidite ligand and its chiral Ni complex with a suitable cavity. By switching the work-up of the reaction involved, the present strategy may be extended to subsequent downstream transformations of silyl ether-containing oxasilacycles to give chiral o-tolyl arylmethanols with high ees and quantitative conversions. A series of experimental results support that the strategy of silicon-mediated organic synthesis controlled by nickel catalysis demonstrates a powerful potential for the facile synthesis of chiral alcohols and its drug-like derivatives. Finally, mechanistic and computational investigations of the nickel-catalyzed Si–C bond activation offer insights into the origin of the observed stereoselective outcome, and the density functional theory calculation shows that the nickel-controlled Si–C(sp2) bond activation enables the controllable migratory insertion of benzaldehyde into the Ni–Si bond, which is recognized as the enantioselectivity-determining step.

Enantio‐ and Diastereoselective Copper‐Catalyzed Allylboration of Alkynes with Allylic gem‐Dichlorides

AbstractAllylic gem‐dichlorides are shown to be efficient substrates for catalytic asymmetric allylboration of alkynes. The method employs a chiral NHC−Cu catalyst capable of generating in a single step chiral skipped dienes bearing a Z‐alkenyl chloride, a trisubstituted E‐alkenyl boronate and a bis‐allylic stereocenter with excellent levels of chemo‐, regio‐ enantio‐ and diastereoselectivity. This high degree of functionalization makes these products versatile building blocks as illustrated with the synthesis of several optically active compounds. DFT calculations support the key presence of a metal cation bridge ligand–substrate interaction and account for the stereoselectivity outcome.

Enantio- and Diastereoselective Copper-Catalyzed Allylboration of Alkynes with Allylic gem-Dichlorides.

Allylic gem‐dichlorides are shown to be efficient substrates for catalytic asymmetric allylboration of alkynes. The method employs a chiral NHC−Cu catalyst capable of generating in a single step chiral skipped dienes bearing a Z‐alkenyl chloride, a trisubstituted E‐alkenyl boronate and a bis‐allylic stereocenter with excellent levels of chemo‐, regio‐ enantio‐ and diastereoselectivity. This high degree of functionalization makes these products versatile building blocks as illustrated with the synthesis of several optically active compounds. DFT calculations support the key presence of a metal cation bridge ligand–substrate interaction and account for the stereoselectivity outcome.

Role of Anion in Determining the Stereoselectivity of Mg-Ph-BOX-Catalyzed Diels–Alder Reactions: A Computational Study

In the realm of enantioselective Diels–Alder reactions, a role of primary importance is held by Mg-BOX catalysis. The main features of both catalysts and ligand in directing the stereoselective outcome have been extensively studied in several papers mainly through 1H NMR and X-ray diffraction (XRD) techniques. However, over the years, no computational studies have been reported to support the models proposed to rationalize the observed stereoselectivity for the reaction between 3-acryloyl-1,3-oxazolidin-2-one and cyclopentadiene catalyzed by the BOX ligand (R,R)-(+)-2,2′-isopropylidenebis(4-phenyl-2-oxazoline) and Mg(II) salts. To approach the problem, we performed a density functional theory (DFT) computational study, aiming to locate the preferred transitions states deriving from these proposed models, but we only found a correspondence in selectivities for the reaction catalyzed by Mg(OTf)2, where the model suggests an octahedral complex with the two triflate anions coordinating magnesium. For the other cases [i.e., Mg(ClO4)2, Mg(ClO4)2·2H2O, and MgI2·I2], the commonly accepted tetrahedral or octahedral models suggest no involvement of the perchlorate or iodide anions, but the corresponding calculations did not reproduce the experimental selectivities. Only when we considered also in these cases coordination complexes involving their presence, the observed selectivities were reproduced, thus opening new insights to better understand the role and the action of the counterion to determine the stereochemical outcome of these reactions.

ProPhenol Derived Ligands to Simultaneously Coordinate a Main-Group Metal and a Transition Metal: Application to a Zn-Cu Catalyzed Reaction.

A new bifunctional ligand bearing chiral N-heterocyclic carbene (NHC) and prolinol moieties is presented. Utilizing the designed ligand, an in situ formed Cu/Zn hetero-bimetallic complex unlocks the asymmetric allylic alkylation reactions of allyl phosphates with zinc keto-homoenolates, leading to the formation of various γ-vinyl ketones with good regio- and enantio-selectivity. DF sT calculation supports that the chelation of allyl phosphates with catalyst promotes the SN 2' addition and the ligand-substrate steric interactions account for the stereoselective outcome.

Chiral Phosphoric Acid Catalysis: The Terada Model Revisited

Since Akiyama and Terada independently reported the introduction of chiral phosphoric acids (CPAs) as effective catalysts for Mannich-type reactions in 2004, the field of CPA catalysis has grown immensely. Terada reported in 2008 the first example of the activation of aldehydes by a CPA. Based on density functional theory (DFT) calculations, Terada proposed a dual activation mode for this enantioselective aza-ene-type reaction between an aldehyde and an enecarbamate. In this model, hydrogen bonds between the catalyst's hydroxyl group and the carbonyl oxygen and the catalyst's P═O and the formyl proton were observed; the nucleophile then attacks without coordination to the catalyst. This reaction model provided the mechanistic basis for understanding Terada's reaction and many other asymmetric transformations. In the present study, DFT calculations are reported that identify a lower-energy mechanism for this landmark reaction. In this new model, hydrogen bonds between the catalyst's hydroxyl group and the aldehyde oxygen and the catalyst's P═O and the NH group of the enecarbamate are seen. The new model rationalizes the stereoselective outcome of Terada's reaction and offers insight into why a more sterically demanding catalyst gives lower levels of enantioselectivity.

Influence of N‐Substitution in 3‐Alkyl‐3‐hydroxyisoindolin‐1‐ones on the Stereoselectivity of Brønsted Acid‐Catalyzed Synthesis of 3‐Methyleneisoindolin‐1‐ones

AbstractA comprehensive study on the influence of N‐substitution on the stereoselective outcome of the synthesis of 3‐methyleneisoindolin‐1‐ones from 3‐alkyl‐3‐hydroxyisoindolin‐1‐ones is reported. The study was performed on an array of structurally diverse 3‐alkyl‐3‐hydroxyisoindolin‐1‐ones with tunable sizes of N‐substituents. In a methanesulfonic acid‐catalyzed reaction, substrates without N‐substituent (N−H) afforded exclusively the Z‐isomer, while an increase in their size was followed by the formation of a stereoisomeric mixture with the E‐isomer as the major component.

Diastereoselective Synthesis of Spirocyclic Ether from ortho‐Carbonylarylacetylenols via Silver‐Catalyzed Cyclization under Acidic Conditions

Abstractortho‐Carbonylarylacetylenol, can be utilized for the synthesis of several important core structures. In this work, a method is developed for the diastereoselective synthesis of spirocyclic ethers using a silver catalyst under the presence of acid. This protocol can be applied to a variety of substrates resulting in the corresponding products in 35–97% yields with good diastereoselectivity. The proposed reaction mechanisms and stereoselectivity outcome of the corresponding products are investigated using DFT calculation. This current protocol can be applied to a broad range of substrates which would be useful for the creation of libraries of spirocylic ethersmagnified image

Evolution of Routes for Asymmetric Total Synthesis of Cyclocitrinol Enabled by Type II [5+2] Cycloaddition†

Main observation and conclusionThe asymmetric total synthesis of an unusual C25 steroid containing a unique bicyclo[4.4.1]undecene A/B ring system, resulting in the synthesis of cyclocitrinol (1) and its isomer Δ8,14‐cyclocitrinol (38), is reported. Initial attempts to construct the synthetically challenging bicyclo[4.4.1]undecene A/B ring system using a type II [5+2] cycloaddition showed that a chiral substituent at the allylic position of the alkene (C6, cyclocitrinol numbering) controlled the stereoselective outcome of the cycloaddition reaction. Late‐stage migration of the tetrasubstituted C8–C14 double bond in Δ8,14‐cyclocitrinol (38) to obtain cyclocitrinol (1) proved challenging, inspiring an alternative approach. The chiral β‐CH2OR group on the allylic substituent at C6 played a pivotal role both in controlling the diastereoselectivity of the type II [5+2] cycloaddition and retaining the C6 substituent under lithium–amine conditions.

Statistical Analysis of Glycosylation Reactions.

Chemical synthesis is one of the practical approaches to access carbohydrate-based natural products and their derivatives with high quality and in a large quantity. However, stereoselectivity during the glycosylation reaction is the main challenge because the reaction can generate both α- and β-glycosides. The main focus of the present article is the concept of recent mechanistic studies that have applied statistical analysis and quantitation for defining stereoselective changes during the reaction process. Based on experimental evidence, a detailed discussion associated with the mechanism and degree of influence affecting the stereoselective outcome of glycosylation is included.

Grafting of Lanthanum Complexes on a Functionalized Graphene Surface: Theoretical Investigation on Ethylene and 1,3-Butadiene Homo- and Co-Polymerization.

In this contribution, we describe the use of graphene as an efficient catalyst support and the role it plays in increasing the Lewis acidity of the supported metal complexes. By a density functional theory study, we show that the [La(N(SiMe3 )2 )3 ] complex can be easily grafted on graphene-OH and -COOH functionalized surfaces. Two stable mono-grafted compounds, (gO)-[La(N(SiMe3 )2 )2 ] and (gOO)-[La(N(SiMe3 )2 )2 ], are formed, behaving as stronger Lewis acids than the previously reported silica grafted analogues. To study the role of the graphene support in catalysis, we also computed the catalytic activity of the alkylated (gO)-[La(CH3 )2 ] and (gOO)-[La(CH3 )2 ] complexes in the ethylene and 1,3-butadiene homo- and co-polymerization reactions. Both compounds are efficient catalysts for the homo-polymerization of the ethylene and 1,3-butadiene. For the 1,3-butadiene homo-polymerization, the stereoselectivity outcome of the reaction differs according to the grafting site. The results computed for the co-polymerization reaction, finally, show that the high stability of the allylic products leads to the formation of block copolymers.

Double Enzyme-Catalyzed One-Pot Synthesis of Enantiocomplementary Vicinal Fluoro Alcohols.

A double-enzyme-catalyzed strategy for the synthesis of enantiocomplementary vicinal fluoro alcohols through a one-pot, three-step process including lipase-catalyzed hydrolysis, spontaneous decarboxylative fluorination, and subsequent ketoreductase-catalyzed reduction was developed. With this approach, β-ketonic esters were converted to the corresponding vicinal fluoro alcohols with high isolated yields (up to 92%) and stereoselectivities (up to 99%). This new cascade process addresses some issues in comparison with traditional methods such as environmentally hazardous reaction conditions and low stereoselectivity outcome.

Chiral Phosphoric Acid-Catalyzed Enantioselective Direct Arylation of Iminoquinones: A Case Study of the Model Selectivity

Chiral phosphoric acid (CPA)-catalyzed enantioselective arylation reactions have attracted immense attention recently. However, the preferential activation model in the stereodetermining step is controversial, and hence, the origin of enantioselectivity is still far from being understood. Two stereochemical models are provided on the basis of the asymmetric arylations of iminoquinones with naphthylamines (reaction 1) or naphthols (reaction 2) catalyzed by (R/S)-TRIP to explain the high enantioselectivity and the effect of CPAs scaffolds. Unexpectedly, our calculations reveal that substrate naphthylamines or naphthols prefer enantioselective aminal formation model II or 1,4-addition model I, respectively, which is the reverse of Tan's and Xu's model. The different noncovalent and steric interactions between catalysts and substrates are responsible for the observed model preference. Moreover, the enantioselectivity arises from distortion (reaction 1) and noncovalent interactions (reaction 2) that discriminate between the diastereomeric transition states. We further investigated the effect of SPINOL-based CPAs on the enantioselectivity and found that the more rigid skeleton and a smaller binding pocket lead to lower enantioselectivity as compared with that of BINOL-based CPA. The new insights into the reaction activation model rationalize the stereoselectivity outcome of direct asymmetric arylation reactions, and our general model can be extended to related transformations.

Synthesis of 3-deoxy-2-uloses via the indium-mediated allylation reaction

We utilized the indium-mediated allylation reaction for the synthesis of carbohydrate structures containing the 3-deoxy-2-ulose motif, a barely investigated compound class. The stereoselective outcome can be controlled by the presence or absence of a chelating group in α-position to the carbonyl function. By introduction of an UV-active allyl building block, we enabled epimer separation by HPLC towards the synthesis of 3-deoxy-d-glycero-d-galacto-2-nonulose, the carboxyl-reduced analogue of widely distributed 3-deoxy-d-glycero-d-galacto-nonulosonic acid (Kdn). Ozonolysis of the introduced 2-C-methylidenepropan-1-ol motif provided the desired 3-deoxy-2-uloses.Graphical abstract