Asymmetric aldol additions: use of titanium tetrachloride and (-)-sparteine for the soft enolization of N-acyl oxazolidinones, oxazolidinethiones, and thiazolidinethiones.

Asymmetric aldol additions using chlorotitanium enolates of N-acyloxazolidinone, oxazolidinethione, and thiazolidinethione propionates proceed with high diastereoselectivity for the Evans or non-Evans syn product depending on the nature and amount of the base used. With 1 equiv of titanium tetrachloride and 2 equiv of (-)-sparteine as the base or 1 equiv of (-)-sparteine and 1 equiv of N-methyl-2-pyrrolidinone, selectivities of 97:3 to > 99:1 were obtained for the Evans syn aldol products using N-propionyl oxazolidinones, oxazolidinethiones, and thiazolidinethiones. The non-Evans syn aldol adducts are available with the oxazolidinethione and thiazolidinethiones by altering the Lewis acid/amine base ratios. The change in facial selectivity in the aldol additions is proposed to be a result of switching of mechanistic pathways between chelated and nonchelated transition states. The auxiliaries can be reductively removed or cleaved by nucleophilic acyl substitution. Iterative aldol sequences with high diastereoselectivity can also be accomplished.     

The role of achiral pyrazolidinone templates in enantioselective Diels-Alder reactions: scope, limitations, and conformational insights

We have evaluated the role of achiral pyrazolidinone templates in conjunction with chiral Lewis acids in room temperature, enantioselective Diels-Alder cycloadditions. The role of the fluxional N(1) substituent was examined, with the bulky 1-naphthylmethyl group providing enantioselectivities up to 99% ee, while templates with smaller fluxional groups gave lower selectivities. High selectivities were also observed in reactions of 7d with chiral Lewis acids derived from relatively small chiral ligands, suggesting the pyrazolidinone templates are capable of relaying stereochemical information from the ligand to the reaction center. Lewis acids capable of adapting square planar geometries, such as Cu(OTf)2, Cu(ClO4)2, and Pd(ClO4)2, were found to be particularly effective at providing high selectivities. Additionally, substitution at the C-5 position of the pyrazolidinone templates has been shown to be critical for optimal selectivity. Reactions of the optimal pyrazolidinone appended with a number of common dienophiles and various dienes demonstrate the utility of this achiral template. Furthermore, catalytic loadings could be lowered to 2.5 mol % with essentially no loss in selectivity. Pi-Pi interactions were evaluated as a means to explain the unusually high selectivity observed at room temperature. Finally, non-C2-symmetric ligands were employed as a test to determine if chiral relay was operative.     

Conformational change in a urea catalyst induced by sodium cation and its effect on enantioselectivity of a Friedel-Crafts reaction

While developing bis-camphorsulfonyl urea as a hydrogen-bonding catalysts, we discovered that the native conformation of the catalyst is unsuitable for inducing enantioselectivity. By complexing the catalyst with weakly Lewis acidic sodium cations, we were able to change the conformation of the catalyst and attain a significant improvement in the selectivity. We provide structural information from X-ray crystallography to show that the uncomplexed catalyst is indeed in an unfavorable conformation. Infrared and Raman spectroscopic studies show that sodium binds the catalyst through the carbonyl and sulfonyl groups. Simulated IR and Raman spectra match well with the experimentally recorded spectra, thereby corroborating the proposed conformational change. This result shows that weak Lewis acids can be used to tune the conformation of hydrogen-bonding catalysts and enhance the selectivity of reaction catalyzed by these systems.     

Catalytic Regioselective Isomerization of 2,2‐Disubstituted Oxetanes to Homoallylic Alcohols

The selective isomerization of strained heterocyclic compounds is an important tool in organic synthesis. An unprecedented regioselective isomerization of 2,2‐disubstituted oxetanes into homoallylic alcohols is described. The use of tris(pentafluorophenyl)borane (B(C₆F₅)₃)_, a commercially available Lewis acid was key to obtaining good yields and selectivities since other Lewis acids afforded mixtures of isomers and substantial polymerization. The reaction took place under exceptionally mild reaction conditions and very low catalyst loading (0.5 mol %). DFT calculations disclose the mechanistic features of the isomerization and account for the high selectivity displayed by the B(C₆F₅)₃ catalyst. The synthetic applicability of the new reaction is demonstrated by the preparation of γ‐chiral alcohols using iridium‐catalyzed asymmetric hydrogenation.     

Cyclization of 1,5-dienes: an efficient synthesis of beta-Georgywood

In the acid-promoted 1,5-diene cyclization of pseudo- to beta-Georgywood, the cyclization product is obtained with high selectivity in spite of an unfavorable substituent at the C(2)-position of the diene precursor. Preisomerization of the cyclohexene double bond, which occurs in the presence of Br?nsted acids, is suppressed with >1 equiv of MXn-type Lewis acids, whereas RAlX2-type Lewis acids such as >2 equiv of MeAlCl2 have the additional benefit of steering the double bond of the cyclized product into the desired beta-position. Mechanistic studies revealed a crucial participation or nonparticipation of the carbonyl group in the cyclization reaction, depending on the acid family employed, and allowed finally the development of a cyclization reaction catalyzed by MeAlCl2 that can be generated in situ from precatalyst AlMe3.1.     

Efficient chemoselective carboxylation of aromatics to arylcarboxylic acids with a superelectrophilically activated carbon dioxide-Al(2)Cl(6)/Al system

Aromatic carboxylic acids are obtained in good to excellent yield essentially free of diaryl ketones by carboxylation of aromatics with a carbon dioxide-Al(2)Cl(6)/Al system at moderate temperatures (20-80 degrees C). To optimize reaction conditions and study the reaction mechanism, experimental variables including temperature, amount of Al(2)Cl(6)/Al, various Lewis acids, role of metal additive, carbon dioxide pressure, etc. were studied. The carboxylation reaction was found to be stoichiometric rather than catalytic, with aluminum chloride forming a dichloroaluminate of carboxylic acids. Although the carboxylation takes place using AlCl(3) itself, the presence of metal additives, especially Al, increased the yield and selectivity of carboxylic acids. Because it was not possible to distinguish between two possible mechanistic pathways of the reaction on the basis of the experimental results, theoretical calculations using density functional theory (DFT) were also carried out. One possible pathway involves an initial complex between benzene and Al(2)Cl(6), with subsequent formation of organoaluminum intermediates (PhAlCl(2) and PhAl(2)Cl(5)). The other proceeds through the formation of various complexes of CO(2) with aluminum chloride (AlCl(3))(n), n = 1-4. The calculations have shown that the organometallic pathway, leading eventually through the formation of phenylaluminum dichloride, is endothermic by 33 kcal/mol. In contrast, the preferred CO(2)-AlCl(3) complex forms in an exothermic reaction (-6.0 kcal/mol) as does CO(2)AlCl(2)(+). On the basis of both experimental and calculational findings, the most feasible reaction mechanism proposed involves superelectrophilic aluminum chloride activated carbon dioxide reacting with the aromatics in a typical electrophilic substitution.     

Synthesis and Diels-Alder reactions of homochiral 2-sulfinylmaleates with cyclopentadiene

Enantiomerically pure 2-p-tolylsulfinylmaleates 1, 2 and 3 have been readily prepared by Knoevenagel reaction between (S)-menthyl p-toluenesulfinate and glyoxylic acid. Their asymmetric Diels-Alder reactions with cyclopentadiene have been studied under a wide range of uncatalyzed and catalyzed conditions and the stereochemical results have been explained by assuming a steric control approach, in term of S-cis or S-trans favoured conformations. Uncatalyzed Diels-Alder reactions of 1 and some Lewis acid catalyzed Diels-Alder reactions of 2 show high facial and endo selectivities. The facial selectivity of dienophile 2 highly depends on the Lewis acid, whereas reactivity of 1 and 3 is very sensitive to the solvent. These sulfinylmaleates 1, 2 and 3 act as synthetic equivalents of chiral acetylenedicarboxylates in Diels-Alder reactions after basic elimination of the sulfinylic moiety in the resulting adducts.     

Lewis acid- and Bronsted acid-catalyzed stereoselective rearrangement of epoxides derived from himachalenes: access to new chiral polycyclic structures

The acid-catalyzed rearrangement of two enantiomerically pure epoxides derived from sesquiterpernic himachalenes, which are the main components of the essential oil of the Atlas cedar, has been studied using various Lewis and Bronsted acids. Several new polycyclic compounds have been obtained with different selectivities depending upon the catalysts used and the reaction conditions, and were fully characterized by spectroscopic methods. Mechanisms to explain the formation of the different compounds observed in the reaction mixture have also been proposed.     

Pushing the Boundaries of Vinylogous Reactivity: Catalytic Enantioselective Mukaiyama Aldol Reactions of Highly Unsaturated 2‐Silyloxyindoles

The first example of catalytic, enantioselective hypervinylogous Mukaiyama aldol reaction (HVMAR) involving multiply unsaturated 2‐silyloxyindoles is reported. The reaction utilizes a chiral Lewis base‐catalyzed Lewis acid‐mediated technology to deliver homoallylic 3‐polyenylidene 2‐oxindoles with extraordinary levels of regio‐, enantio‐, and geometrical selectivity. This work highlights a subtle yet decisive influence of the indole N‐substituents on the propagation of the vinylogous reactivity space of the donor substrates up to ten bonds away from the origin of the vinylogy effect. Analysis of the ¹³C NMR chemical shifts of the C‐ω remote site within homologous silyloxyindole donors enabled rationalization of the results and easy qualitative prediction of the HVMAR reactivity/inertia toward a given aldehyde acceptor.     

Asymmetric hetero-Diels-Alder reactions of N-sulfinyl dienophiles using chiral bis(oxazoline)-copper(II) and -zinc(II) triflates

Asymmetric hetero-Diels-Alder (HDA) reactions of N-sulfinyl dienophiles using bis(oxazoline)-copper(II) and -zinc(II) triflates are described. The cycloadditions with cyclic and acyclic 1,3-dienes have been studied. In most cases, good enantioselectivities (70-98% ee) and yields (60-85%) were obtained with stoichiometric amounts of the Lewis acids. Cyclic dienes gave the endo adducts as major products, while acyclic dienes provided cis adducts. The HDA adducts have been transformed into N-protected alpha-amino acid methyl esters, amino alcohols, and homoallylic amines. A stereochemical model, which accounts for the enantiofacial selectivity of the HDA reaction by a tetrahedral metal center, has been proposed. Mechanistic studies revealed positive nonlinear effects, assumed to arise from the formation of less-reactive heterochiral complexes. Investigation of the temperature dependence of the enantioselectivity indicated that at least two selective reaction steps exist in the zinc-catalyzed reaction. Reactions run with 10 mol % chiral Lewis acid gave poor yields and selectivities. However, in combination with TMSOTf (100 mol %), high yields (68-86%) and enantioselectivities (97-98% ee) were obtained.     

Synergistic Palladium/Lewis Acid-Catalyzed Regio- and Stereo-divergent Bissilylation of Alkynoates: Scope,Mechanism, and Origin of Selectivity

Transition metal-catalyzed bissilylation reactions of alkynes with disilane reagents have become one of the most straightforward and efficient protocols to rapidly produce structurally diverse alkenyl silicon derivatives. In these reactions, the utilization of unsymmetrical disilane reagents provided the possibilities for reactivity enhancement as well as the synthetic merits in contrast to symmetrical disilane reagents. However, a major yet challenging objective is achieving precise control over the selectivity including the regioselectivity and the cis/trans-selectivity. Herein we realized the first divergent bissilylation of alkynoates with our developed air-stable disilane reagent 8-(2-substituted-1,1,2,2-tetramethyldisilanyl)quinoline (TMDQ) by means of synergistic Pd/Lewis acid catalytic system. The catalytic system precisely dictates the selectivity, resulting in the divergent synthesis of 1,2-bissilyl alkenes. The power of these 1,2-bissilyl alkenes serving as the key synthetic intermediates has been clearly demonstrated by rapid construction of diverse motifs and densely functionalized biologically active compounds. In addition, the origins of the switchable selectivities were well elucidated by experimental and computational studies on the reaction mechanism and were mainly attributed to different ligand steric effects, the use of the specific disilane reagent TMDQ and the different coordination modes of different Lewis acid with alkynoates.     

Mechanism of the Meerwein-Ponndorf-Verley-Oppenauer (MPVO) redox equilibrium on Sn- and Zr-beta zeolite catalysts

The mechanism of the Meerwein-Ponndorf-Verley (MPV) reduction of cyclohexanone with 2-butanol catalyzed by Sn-beta and Zr-beta zeolites has been theoretically investigated using density functional theory (DFT) and the cluster approach. An experimental catalytic study has shown that the active sites in the MPV reaction catalyzed by Sn-beta are the same partially hydrolyzed Sn-OH groups that were found to be active for the Baeyer-Villiger (BV) reaction. The computational study indicates that the mechanism of Sn-beta and Zr-beta catalysis is similar, and involves the following steps: adsorption of both the ketone and the alcohol on the Lewis acid center, deprotonation of the alcohol, carbon-to-carbon hydride transfer, proton transfer from the catalyst, and products exchange. As in the aluminum alkoxide catalyzed reaction, the hydride shift occurs through a six-membered transition state, and the role of the hydrolyzed and therefore more flexible M-OH bond is just to facilitate the initial deprotonation of the alcohol.     

Development of efficient Lewis acid catalysts for intramolecular cycloaddition reactions of ester-tethered substrates

We have developed novel bidentate Lewis acids that efficiently promote the intramolecular cycloaddition reactions of ester-tethered substrates. Bis-aluminated triflic amide derivatives [TfN(AlR(1)R(2))2], which are generated by simply mixing triflic amide and 2 equiv of methyl aluminum or aluminum hydride, catalyzed intramolecular Diels-Alder (DA) reactions of ester-tethered 1,7,9-trienes and intermolecular DA reactions of alpha,beta-unsaturated lactones. We also found that bimetallic Lewis acid derived from 1,1'-biphenyl-2,2'-di(triflyl)amide and dimethylaluminum chloride promoted the intramolecular [3 + 2] cycloaddition reaction of acrylate derivatives having an allylsilane part.     

Phosphine- and nitrogen-containing Lewis base catalyzed highly regioselective and geometric selective cyclization of isatin derived electron-deficient alkenes with ethyl 2,3-butadienoate

An interesting phosphine-containing Lewis base catalyzed highly regioselective [3 + 2] cycloaddition and a novel nitrogen-containing Lewis base catalyzed highly geometric selective [4 + 2] cycloaddition of isatin derived α,β-unsaturated diesters with α-allenic ester have been disclosed to give the corresponding cyclic products in good to excellent yields under mild conditions. A plausible reaction mechanism has also been proposed on the basis of previous literature and our own investigation.     

Super Brønsted acid catalysis

Br?nsted acid catalysis has emerged as a new class of catalysis in modern organic synthesis. However, in order to make the utility of the Br?nsted acid catalysis as broad as the well-developed Lewis acid catalysis, it is desirable to develop Br?nsted acids demonstrating both high reactivities and selectivities. In this feature article, we will present our achievement in the design and development of strong Br?nsted acids and their application to organic reactions. Furthermore, we will describe the Tf(2)NH-catalyzed Mukaiyama aldol reaction of super silyl enol ethers. We also will highlight the differences in reactivity and chemo- and stereo-selectivity between Br?nsted and Lewis acid catalysis.     

Copper‐Catalyzed Electrophilic Etherification of Arylboronic Esters with Isoxazolidines

A copper‐catalyzed electrophilic etherification of arylboronic esters is reported. Isoxazolidines are utilized as easily available and stable [RO]⁺ surrogates to give 1,3‐amino aryl ethers. The O‐selective arylation of isoxazolidines takes place without causing competitive N‐arylation. In contrast to previously reported anionic conditions, our copper‐catalyzed conditions are mild enough to achieve high functional group tolerance. Preliminary mechanistic studies and DFT calculations support that the reaction proceeds via a transmetalation/oxidative addition pathway, followed by a Lewis acid‐promoted reductive elimination to induce the crucial O‐selectivity.     

Fe-catalyzed regioselective Friedel–Crafts hydroxyalkylation of N-substituted glyoxylamide with indoles

An efficient regioselective Friedel–Crafts hydroxyalkylation of N-substituted glyoxylamide with various indoles catalyzed by Lewis acids was developed. The reactions proceeded smoothly at room temperature and the 2-hydroxy-2-(1H-indol-3-yl)-N-substituted acetamide resulted from the reactions catalyzed by FeSO_4 were synthesized in excellent yields(up to 93%). While the bisindole compounds were obtained when FeCl_3 was used as a catalyst in excellent yields(up to 92%). A possible mechanism was proposed.     

Endo-selective Diels-Alder reaction of methacrylonitrile: application to the synthesis of Georgywood

Diels-Alder reactions of alkyl-substituted dienes with acrylonitriles give good yields and endo-selectivities if catalyzed by (organo)aluminum, (organo)boron or gallium halides. The activity of these group IIIa Lewis acids in this reaction correlates with the coordination strength of their nitrile complexes, which deactivate Lewis acids sufficiently, so that the subsequently added diene partner undergoes the Diels-Alder reaction without serious side-reactions. Boron trichloride is the most effective catalyst for this purpose. This method gives the best endo/exo-ratios reported so far for these components and was applied in the selective synthesis of the olfactory vector of Georgywood^®.     

Quantum mechanical models correlating structure with selectivity: predicting the enantioselectivity of beta-amino alcohol catalysts in aldehyde alkylation

Quantitative structure selectivity relationship (QSSR) models are described that provide consistently reliable predictions for the asymmetric addition of Et2Zn to PhCHO catalyzed by beta-amino alcohols. Statistically valid two-variable linear regression models that correlate the structures of the chiral catalysts with their enantioselectivities are obtained from three-dimensional physical property grids. The strength of the present method is that statistical models obtained from a small set of experimentally determined selectivities and relatively simple theoretical calculations yield selectivity predictions that are as accurate as those derived from higher-level calculations of transition-structure energies. Only minutes of computing time are required. Simple models are obtained which permit straightforward physical interpretation and generate realistic predictions.