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The fluorine atom is a powerful, yet often enigmatic influence on chemical reactions. True to form, fluorine was recently discovered to effect diastereodivergence in an enantioselective aza-Henry reaction, resulting in a very rare case of syn-β-amino nitroalkane products. More bewildering was the observation of an apparent hierarchy of substituents within this substrate-controlled behavior: PhFalkyl. These cases have now been examined comprehensively by computational methods, including both non-fluorinated and a-fluoro nitronate additions to aldimines catalyzed by a chiral bis(amidine) [BAM] proton complex. This study revealed the network of non-covalent interactions that dictate anti- (a-aryl) vs. syn-selectivity (a-alkyl) using α-fluoronitronate nucleophiles, and an underlying secondary orbital interaction between fluorine and the activated azomethine.

Hydroamidation of carbon-carbon double bonds is an attractive strategy for installing nitrogen functionality into molecular scaffolds and, with it, increasing molecular complexity. To date, metal-based approaches have dominated this area of chemical synthesis, despite the drawbacks of air and moisture sensitivity, limited functional group tolerance, toxicity, and/or high cost often associated with using metals. Here, in offering an alternative solution, we disclose an operationally simple, metal-free, one-pot, regioselective, multicomponent synthetic procedure for the hydroamidation of carbon-carbon double bonds. This method features mild reaction conditions and utilizes isocyanides and vinyl ethers for the rapid and modular synthesis of privileged α-oxygenated amide scaffolds. In unraveling the mechanistic underpinning of this non-metal-based reactivity, we present kinetic solvent isotope effect studies, variable time normalization analysis, and density functional theory computations offering insight into the mechanism of this multistep catalytic hydroamidation process.

Recently, our group reported that enone and ketone functional groups, upon photoexcitation, can direct site-selective sp3 C-H fluorination in terpenoid derivatives. How this transformation actually occurred remained mysterious, as a significant number of mechanistic possibilities came to mind. Herein, we report a comprehensive study describing the reaction mechanism through kinetic studies, isotope-labeling experiments, 19F NMR, electrochemical studies, synthetic probes, and computational experiments. To our surprise, the mechanism suggests intermolecular hydrogen atom transfer (HAT) chemistry is at play, rather than classical Norrish hydrogen atom abstraction as initially conceived. What is more, we discovered a unique role for photopromoters such as benzil and related compounds that necessitates their chemical transformation through fluorination in order to be effective. Our findings provide documentation of an unusual form of directed HAT and are of crucial importance for defining the necessary parameters for the development of future methods.

An unsymmetrical guanidine-cyclopropenimine proton sponge DAGUN and the related BF2 -chelate DAGBO are reported. Insight into the structural, electronic, bonding and photophysical properties of these two molecules are presented. Joint experimental and theoretical studies reveal the protonated form of DAGUN possesses an intramolecular N⋅⋅⋅H-N hydrogen bond which affords a high experimental pKBH+ of 26.6 (computed=26.3). Photophysical studies show that in solution DAGUN displays a green emission at 534 nm, with a large Stokes shift of 235 nm (14,718 cm-1 ). In contrast, the conjugate acid DAGUN-H+ is only weakly emissive due to attenuated intramolecular charge transfer. X-ray diffraction studies reveal that DAGBO contains a stable tetracoordinate boronium cation, reminiscent of the well-established BODIPY family of dyes. In solution, DAGBO exhibits a strong blue emission at 450 nm coupled with a large Stokes shift (Δλ=158 nm, Δν=11,957 cm-1 ) and quantum yield of 62 %, upon excitation at 293 nm. DAGBO sets the stage as the first entry into a new class of boron-difluoride diaminonaphthalenes (BOFDANs) that represent highly fluorescent and tunable next-generation dyes with future promise for biosensing and bioimaging applications.

Pyranylation and glycosylation are pivotal for accessing a myriad of natural products, pharmaceuticals, and drug candidates. Catalytic approaches for enabling these transformations are of utmost importance and integral to advancing this area of synthesis. In exploring this chemical space, a combined experimental and computational mechanistic study of pyranylation and 2-deoxygalactosylation catalyzed by a cationic thiourea organocatalyst is reported. To this end, a thiourea-cyclopropenium organocatalyst was employed as a model system in combination with an arsenal of mechanistic techniques, including 13C kinetic isotope effect experiments, deuterated labeling studies, variable-temperature 1H NMR spectroscopy, and density functional theory calculations. From these studies, two distinct reaction pathways were identified for this transformation corresponding to either dual hydrogen bond (H-bond) activation or Bronsted acid catalysis. The former involving thiourea orchestrated bifurcated hydrogen bonding proceeded in an asynchronous concerted fashion. In contrast, the latter stepwise mechanism involving Bronsted acid catalysis hinged upon the formation of an oxocarbenium intermediate accompanied by subsequent alcohol addition.

A pair of chiral bis(amidine) [BAM] proton complexes provide reagent (catalyst)-controlled, highly diastereo- and enantioselective direct aza-Henry reactions leading to α-alkyl-substituted α,β-diamino esters. A C(2)-symmetric ligand provides high anti-selectivity, while a non-symmetric congener exhibits syn-selectivity in this example of diastereodivergent, enantioselective catalysis. A detailed computational analysis is reported for the first time, one that supports distinct models for selectivity resulting from the more hindered binding cavity of the C(1)-symmetric ligand. Binding in this congested pocket accommodates four hydrogen bond contacts among ligand and substrates, ultimately favoring a pre-syn arrangement highlighted by pyridinium-azomethine activation, and quinolinium-nitronate activation. The complementary transition states reveal a wide range of alternatives. Comparing the C(1) and C(2)-symmetric catalysts highlights distinct electrophile binding orientations despite their common hydrogen bond donor-acceptor features. Among the factors driving unusual high syn-diastereoselection are favorable dispersion forces that leverage the anthracenyl substituent of the C(1)-symmetric ligand.

The unprecedented synthesis, single-crystal X-ray structure, and first catalytic application of a dicarbene-Ag(I) complex [Ag(BAC)2][CO2CF3] (BAC = bis(diisopropyl)aminocyclopropenylidene) is reported. This novel complex provides a versatile catalytic platform for selective aerobic oxidation of benzylic alcohols to aldehyde or ketone products in high yields. Ease of experimental execution coupled with the use of abundant atmospheric molecular oxygen as an oxidant and low catalyst loading are inherit strengths of these oxidations.

A metal-free synthetic protocol for azo compound formation by the direct oxidation of hydrazine HN–NH bonds to azo group functionality catalyzed by molecular iodine is disclosed. The strengths of this reactivity include rapid reaction times, low catalyst loadings, use of ambient dioxygen as a stoichiometric oxidant, and ease of experimental set-up and azo product isolation. Mechanistic studies and density functional theory computations offering insight into this reactivity, as well as the events leading to azo group formation are presented. Collectively, this study expands the potential of main-group element iodine as an inexpensive catalyst, while delivering a useful transformation for forming azo compounds.

The application of cyclopropenium ion as a phase transfer catalyst for benzylic fluorination in high yields is reported. Integral to the mechanisms of these fluorination reactions was the role of in situ derived cyclopropenium fluoride complexes, the existence of which was supported by 1H, 19F NMR and UV–Vis spectroscopy. Density functional theory calculations were applied to gain insight into the mechanism of these reactions.

The zinc hydride NacNacZnH (2) (NacNac = [Ar′NC(Me)CHC(Me)NAr′]−, Ar′ = 2,6-Me2C6H3) catalyzes regioselective hydrosilylation and hydroboration of pyridines, including the hydroboration of phenanthroline. Mechanistic studies of hydrosilylation, including labeling, kinetic analysis, and density functional theory calculations, suggest the possibility of a reaction pathway based on hydride transfer from an out-of-sphere activated silane.

The use of a cyclopropenium cation as a phase-transfer catalyst for O-silyl ether deprotection is reported. Mechanistic insight into this deprotection methodology derived by linear free-energy relationships (LFER), quantum theory of atoms in molecules (QTAIM), and density functional theory (DFT) calculations are also provided.

This work unveils the reactivity patterns, as well as ligand and additive effect on alkali-metal-base-catalyzed transfer hydrogenation of ketones. Crucially to this reactivity is the presence of a Lewis acid (alkali cation), as opposed to a simple base effect. With aryl ketones, the observed reactivity order is Na+ >Li+ >K+ , whereas for aliphatic substrates it follows the expected Lewis acidity, Li+ >Na+ >K+ . Importantly, the reactivity pattern can be drastically changed by adding ligands and additives. Kinetic, labelling, and competition experiments as well as DFT calculations suggested that the reaction proceeds through a concerted direct hydride-transfer mechanism, originally suggested by Woodward. The lithium cation was found to be intrinsically more active than heavier congeners, but in the case of aryl ketones a decrease in reaction rate was observed at ≈40 % conversion with lithium cations. Noncovalent-interaction analysis revealed that this deceleration effect originated from specific noncovalent interactions between the aryl moiety of 1-phenylethanol and the carbonyl group of acetophenone, which stabilize the product in the coordination sphere of lithium and thus poison the catalyst. The ligand/additive effect is a complicated phenomenon that includes a combination of several factors, such as the decrease of activation energy by ligation (confirmed by distortion/interaction calculations of N,N,N',N'-tetramethylethylenediamine, TMEDA) and the change in relative stabilization of reagents and substrates in the solution and the coordination sphere of the metal. Finally, we observed that lithium-base-catalyzed transfer hydrogenation can be further facilitated by the addition of an inexpensive and benign reagent, LiCl, which likely operates by re-initiating the reaction on a new lithium center.

A tricyclic chiral auxiliary, prepared from the enzymatically derived cis-arene dihydrodiol metabolite of toluene, was investigated as a means of asymmetric induction in several different reactions. The auxiliary was converted to an oxaziridine, and its utility in hydroxylation, providing low levels of enantiomeric excess, was compared with that of Davis’s oxaziridine. Insight into the origin of stereoinduction in this reaction is provided and is based on computational Monte Carlo Multiple Minimum (MCMM) searches using the OPLS3 force field. The use of the auxiliary group in the alkylation of appended esters proved disappointing. Diels-Alder cycloaddition of an acrylate, derived from the auxiliary group, with cyclohexadiene furnished a mixture of diastereomeric adducts in essentially equal amounts. The adducts were separated and the corresponding enantiomeric residues were isolated with good enantiomeric excess. Evidence of reasonable levels of asymmetric induction in the above processes was lacking. Experimental and spectral data are provided for all key compounds.

The role of cooperative effects arising from noncovalent attractive interactions as a vital factor governing stereoinduction in chiral H-bond catalyzed aza-Henry reactions is reported. Supporting this finding were density functional theory (DFT) calculations which revealed a shape and size dependency existed between the catalyst and substrates that when matched lead to high enantioselectivity, as reflected by favorable activation parameters. Associated with optimal catalyst and substrate pairing were a closed catalytic binding pocket and a synclinal orientation of the substrates that reinforced favorable stereoelectronic effects and dispersive type forces. Meanwhile, unfavorable steric interactions were found to be a dominant effect controlling diastereoselection.

An integral part of modern organocatalysis is the development and application of thiourea catalysts. Here, as part of our program aimed at developing cyclopropenium catalysts, the synthesis of a thiourea-cyclopropenium organocatalyst with both cationic hydrogen-bond donor and electrostatic character is reported. The utility of the this thiourea organocatalyst is showcased in pyranylation reactions employing phenols, primary, secondary, and tertiary alcohols under operationally simple and mild reaction conditions for a broad substrate scope. The addition of benzoic acid as a co-catalyst facilitating cooperative Bronsted acid catalysis was found to be valuable for reactions involving phenols and higher substituted alcohols. Mechanistic investigations, including kinetic and 1H NMR binding studies in conjunction with density function theory calculations, are described that collectively support a Bronsted acid mode of catalysis.

Charge-enhanced catalysis has emerged as a powerful alternative to the mainstream use of neutral catalysis. With this in mind, we report a catalytic Friedel‒Crafts alkylation method catalyzed by a charged thiourea incorporating a cationic cyclopropenium moiety. Mechanistic studies, including density functional theory computational calculations, variable time normalization analysis, and 1H NMR binding studies, collectively reveal this charge-enhanced reactivity proceeds by a dual hydrogen bond-mediated LUMO-lowering mode of substrate activation. Key to these findings is the observed steady-state concentration of the catalyst with in situ derived monomeric catalytic species predominating under the reaction conditions.

A computationally based design and synthesis of a point chiral seven-membered ring guanidine organocatalyst is reported. The application of this catalyst in asymmetric vinylogous aldol reactions, to form optically active γ-butenolide products with dr’s and er’s up to 90:10 and 97:3 is described.

The synthesis of a solid, bench-stable, strong organic Brønsted acid with a computed pKa of 0.9 is reported. An X-ray crystal structure and DFT calculations are provided which offer insight into the bonding of this acid. The application of this strong organic Brønsted acid as a catalyst for the intermolecular hydroamination of unactivated alkenes and as an activator for Au(I)-catalyzed alkyne hydroamination with anilines is described.

The mechanism of the HQuin-BAM (1) catalyzed aza-Henry reaction between nitromethane and N-Boc-phenylaldimine was studied using density functional theory (DFT). Deprotonation of nitromethane by the catalyst was revealed to be the rate-limiting step, and C···C bond formation was found to be enantio-determining. The catalyst, in addition to acting as a Bronsted base, served to simultaneously activate both the electrophile and the nucleophile through hydrogen bonding during C···C bond formation and is thus essential for both reaction rate and selectivity. Analysis of the hydrogen bonding interactions revealed that there was a strong preference for the formation of a homonuclear positive-charge-assisted hydrogen bond (homonuclear (+)CAHB), which in turn governed the relative orientation of substrate binding. Furthermore, a direct correlation between the dihedral angle (θNCCN) of the reacting substrates and facial selectivity was found. This relationship between θ and facial selectivity was found to be a conse...

We have prepared two new diastereoisomeric 2-aza-5-phosphabicyclo[2.2.1]heptanes from naturally occurring trans-4-hydroxy-l-proline in six chemical operations. These syntheses are concise and highly efficient, with straightforward purification. When we used these chiral phosphines as catalysts for reactions of γ-substituted allenoates with imines, we obtained enantiomerically enriched pyrrolines in good yields with excellent enantioselectivities. These two diastereoisomeric phosphines functioned as pseudoenantiomers, providing their chiral pyrrolines with opposite absolute configurations.

Reduction of the cationic Ge(II) complex [dimpyrGeCl][GeCl3] (dimpyr=2,6-(ArN=CMe)2NC5H3, Ar=2,6-iPr2C6H3) with potassium graphite in benzene affords an air sensitive, dark green compound of Ge(0), [dimpyrGe], which is stabilized by a bis(imino)pyridine platform. This compound is the first example of a complex of a zero-valent Group 14 element that does not contain a carbene or carbenoid ligand. This species has a singlet ground state. DFT studies revealed partial delocalization of one of the Ge lone pairs over the π*(C=N) orbitals of the imines. This delocalization results in a partial multiple-bond character between the Ge atom and imine nitrogen atoms, a fact supported by the X-ray crystallography and IR spectroscopy data.

Diastereoselective induction of planar chirality in ferrocenes often employs chiral sulfur-, carbon- or phosphorus-based directing groups. The origin of stereoselectivity in these reactions may be classified as (a) cyclopentadiene (Cp) ring-con- trolled or (b) base-controlled. These two categories are represented by auxiliaries that typically have stereogenic centers a or g to the ferrocene core, re- spectively. In this study, it is shown that (� )-2-ferro- cenyl-1S-triethylsilyloxy-7aS-hexahydropyrroloA c)imidazol-3-one, the anti-epimer of the previously reported syn-(1R,7aS) substrate, induces lithiation of the pro-Rp rather than the pro-Sp Cp hydrogen in > 95:5 dr, leading to enantiomers of the syn-derived planar chiral imidazolones upon electrophile quench and elimination. This outcome provides a practical way to prepare planar chiral enantio- mers in this series without having to synthesize a more expensive d-proline-derived starting materi- al, since both the syn and anti starting materials are available from a common l-proline-derived inter- mediate. The origin of stereoselectivity in lithiation of the syn and anti epimers, which have b,g-stereo- genic centers, appears to be driven primarily by the conformational bias exerted by the b-silyloxy moiety in each chiral auxiliary, which positions the urea carbonyl within the proximity of one of the two prochiral ortho Cp hydrogens. As such, stereo- selectivity is likely Cp ring-controlled for both com- pounds despite their lack of a-ferrocenyl stereogen- ic centers. This conclusion is supported by the in- sensitivity of lithiation selectivity to the bulkiness of the base, comparisons of enantiomers, deuteration experiments, nOe difference studies, and computa- tional modeling of the ground states and lithiation transition states for both substrates.

A Ag(I)-catalyzed synthesis of chiral C(3)-substituted phthalides (8a–f) via a Sakurai–Hosomi allylation/transesterification reaction is described (ee ≤86%). A notable feature of this reaction is that it utilizes ortho-substituted aldehydes, which are a class of compounds that generally afford poor levels of stereoinduction when applying most known catalytic asymmetric allylation approaches. It was also found that elongation of the n-alkyl chain length (R1, up to n=6; R2=H) of the starting alkyl 2-formylbenzoates (7g–i) improved the enantiomeric excess (ee) of the product.

Bis(diisopropylamino)cyclopropenimine-substituted bis-protonated proton sponge (BDC) is a useful phase-transfer catalyst for the alkylation of compound (I) with a range of alkyl halides.

by John F. Trant, Lee Belding, Travis Dudding, and Tomas Hudlicky*Department of Chemistry and Centre for Biotechnology, Brock University, 500 Glenridge Avenue,St Catharines ON, L2S 3A1, Canada(phone: þ1905688-5550 (ext. 3406); fax: þ1905682-9020; e-mail: thudlicky@brocku.ca)DedicatedtoProfessorDieterSeebachontheoccasionofhis75thbirthdayandinrecognitionofhismanycontributions to our disciplineThe Diels Alder reaction can reliably provide the expected endo-product in the presence ofsecondary orbital overlap. It can be considerably more difficult to access a single enantiomer of the exo-product. In this paper, a d-chiro-inositol derivative is used as a chiral tether to facilitate the regio-,diastereo-, and enatioselective cycloaddition between cinnamic acid and hexa-3,5-dienoic acid. TheDiels Alder reaction between these two substrates, or their respective esters, does not occur underthermal conditions. Because of the ease of removal of the chiral tether from the resulting cyclohexene,this approach could provide a viable technique to access otherwise unavailable systems.

A sequential (R)-BINAP·AgIF (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) (6–10 mol %), and (Ph3P)2PdIICl2 (bis(triphenylphosphine)palladium(II) dichloride) (2 mol %) catalyzed asymmetric Sakurai–Hosomi–Yamamoto allylation/Mizoroki–Heck reaction that affords C1-chiral 3-methylene-indan-1-ols with enantiomeric excess (ee) up to 80% is reported. Notably, this protocol allows for the use of various o-substituted benzaldehydes and allyltrimethoxysilane. It was also discovered that the presence of electron-rich groups had no effect on the enantioselectivity of the reaction, whereas electron-withdrawing groups lead to erosion in product ee.

Alkene difunctionalization reactions are important in organic synthesis. We have recently shown that copper(II) complexes can promote and catalyze intramolecular alkene aminooxygenation, carboamination, and diamination reactions. In this contribution, we report a combined experimental and theoretical examination of the mechanism of the copper(II)-promoted olefin aminooxygenation reaction. Kinetics experiments revealed a mechanistic pathway involving an equilibrium reaction between a copper(II) carboxylate complex and the γ-alkenyl sulfonamide substrate and a rate-limiting intramolecular cis-addition of N-Cu across the olefin. Kinetic isotope effect studies support that the cis-aminocupration is the rate-determining step. UV/Vis spectra support a role for the base in the break-up of copper(II) carboxylate dimer to monomeric species. Electron paramagnetic resonance (EPR) spectra provide evidence for a kinetically competent N-Cu intermediate with a Cu(II) oxidation state. Due to the highly similar stereochemical and reactivity trends among the Cu(II)-promoted and catalyzed alkene difunctionalization reactions we have developed, the cis-aminocupration mechanism can reasonably be generalized across the reaction class. The methods and findings disclosed in this report should also prove valuable to the mechanism analysis and optimization of other copper(II) carboxylate promoted reactions, especially those that take place in aprotic organic solvents.

The use of a bis(diisopropylamino)cyclopropenimine-substituted bis-protonated proton sponge as a bifunctional phase-transfer catalyst is reported. Experimental studies and DFT calculations suggest it operates simultaneously as a hydrogen bond donor and a phase-transfer catalyst, facilitating the movement of charged intermediates from the interface to the organic phase via favorable partitioning of hydrophilic/hydrophobic surface areas, resulting in high catalytic activity.

Previously we reported the ability of trypsin to mediate the cross-linking of alkoxysily-functionalized silicone polymers. Although enzymes and silicon-containing compounds are not necessarily incompatible species, the exact mechanism of how enzymes process silicon substrates is not fully understood. The focus of this current work was to examine the reaction kinetics associated with the processing of an alkoxysilane substrate by enzymes using 29 Si NMR so as to gain a greater insight into the actual reaction mechanism, especially those involving more complex silicone systems. A series of time course 29 Si NMR experiments using D 2 O revealed that the trypsin-mediated hydrolysis of a single alkoxy moiety in water is a pseudo-first order reaction. The relative effect of the enzyme was determined to be β = 3.549 while the relative effect of water was γ = 3.325. Prolonged contact with phenyltrimethoxysilane was not sufficiently deleterious to the enzyme and did not induce the complete and irreversible denaturation of trypsin. Computational evidence suggests that while in the active site of the enzyme, serine addition to silicon to forms a pentacoordinate species and is favoured over histidine addition.

A remarkable example of inverse-temperature-dependent diastereoselectivity was uncovered while investigating the addition of Grignard reagents to a 3-hydroxytetrahydrofurfural. The free hydroxyl group in the tetrahydrofurfural was found to play a key role in these processes, a result corroborated through a series of DFT calculations that also highlighted an entropic preference for the formation of one diastereomer.

The phosphine-catalyzed addition of 2,3-butadienoates to aldehydes has been extended to the formation of disubstituted dihydro-2-pyrones. The requisite shift in equilibrium of the intermediate zwitterionic beta-phosphonium dienolates toward the s-cis intermediate was accomplished through the use of a Brønsted acid additive, which disrupts the favorable Coulombic interaction present in the s-trans intermediate. The detailed nature of the synergistic interactions involving the Brønsted acid additives and phosphine involved in the formation of s-cis beta-phosphonium dienolates was analyzed through a series of DFT calculations. Unlike previously reported annulations of aldehydes with allenoates, where trialkylphosphines are optimal catalysts, in this study triphenylphosphine was also found for the first time to be a suitable catalyst for the synthesis of dihydropyrones. This method provides a one-step route toward functionalized dihydropyrones from simple, stable starting materials. In addition, new reaction pathways of phosphine-catalyzed allene annulations are unveiled, with the formation of dihydropyrones being the first example of dual activation in this sphere.

The mechanism of the catalytic, asymmetric α-bromination of acid chlorides is probed through a series of crossover experiments, ion-pairing tests, and kinetic resolution studies to shed light on the factors that contribute to, and limit the production of, optically-active α-bromo esters. In order to understand better the observed sense of induction, as well as the high degree of enantiomeric excess exhibited by these products, extensive molecular modeling is employed on the relevant transition states. Finally, the usefulness of the α-bromo ester products is demonstrated by their simple derivatization into chiral epoxides.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

A computationally based design and synthesis of a point chiral seven-membered ring guanidine organocatalyst is reported. The application of this catalyst in asymmetric vinylogous aldol reactions, to form optically active γ-butenolide products with dr’s and er’s up to 90:10 and 97:3 is described.

Two diastereoisomeric 2-aza-5-phosphabicyclo[2.2.1]heptanes (I) and (II) are prepared and used as catalysts for the synthesis of enantiomerically enriched pyrrolines with opposite absolute configurations.

The catalytic asymmetric thiazolium- and triazolium-catalyzed benzoin condensations of aldehydes and ketones were studied with computational methods. Transition-state geometries were optimized by using Morokuma's IMOMO [integrated MO (molecular orbital) + MO method] variation of ONIOM ( n -layered integrated molecular orbital method) with a combination of B3LYP/6–31G(d) and AM1 levels of theory, and final transition-state energies were computed with single-point B3LYP/6–31G(d) calculations. Correlations between experiment and theory were found, and the origins of stereoselection were identified. Thiazolium catalysts were predicted to be less selective then triazolium catalysts, a trend also found experimentally.

We present molecular mechanics (MM) calculations as models of activated complexes for the β-lactam forming [2+2] cycloaddition between imino ester 4 and the zwitterionic intermediates derived from ketenes and various chiral nucleophilic catalysts. Our method employs the use of Monte Carlo conformational searches utilizing the MMFF force field contained within the Macromodel program. These models accurately predict the sense of stereochemical induction observed experimentally. Also, the predicted energetic differences for minima leading to (R) or (S)-derived ketene facial selectivity correlate in a general sense with the magnitude of the enantioselectivity. This work establishes that our approach represents a viable method for the design of new nucleophilic catalysts a priori using MM calculations.

We report a new method for the catalytic, asymmetric synthesis of beta-substituted aspartic acid derivatives in which the nucleophilic catalyst serves up to four discrete roles in a one-pot procedure: catalytic dehydrohalogenation of acid chlorides to form ketenes; catalytic dehydrohalogenation of alpha-chloroamines to form the corresponding imines; catalyzed [2 + 2]-cycloaddition to produce intermediate acyl beta-lactams; and finally, nucleophilic ring opening to afford optically enriched beta-substituted aspartic acids in high enantioselectivity and diastereoselectivity.

The straightforward synthesis of a class of nitrogen-based phase-transfer catalysts (PTCs) having markedly dissociated anions due to interionic donor-donor "ion pair strain" and use for catalyzing benzylation and benzylic fluorination is reported. Provided also is insight into the bonding of disubstituted N- vs so-called divalent carbene-stablized N(I)-centered cations and the unprecedented finding of a cyclopropenium based C-H···πaryl interaction.

Methodology for the practical synthesis of nonnatural amino acids has been developed through the catalytic, asymmetric alkylation of alpha-imino esters and N,O-acetals by enol silanes, ketene acetals, alkenes, and allylsilanes using chiral transition metal-phosphine complexes as catalysts (1-5 mol %). The alkylation products, which are prepared with high enantioselectivity (up to 99% ee) and diastereoselectivity (up to 25:1/anti:syn), are protected nonnatural amino acids that represent potential precursors to natural products and pharmaceuticals. A kinetic analysis of the catalyzed reaction of alkenes with alpha-imino esters is presented to shed light on the mechanism of this reaction.

We report a catalytic asymmetric reaction process that involves the use of solid-phase reagents and catalysts that constitute the packing of a series of "reaction columns". This process was applied to the catalytic asymmetric synthesis of beta-lactams, to yield pure products with excellent enantio- and diastereoselectivity. We have identified several advantages to conducting chemical reactions on sequential columns, including ease of catalyst and reagent recovery and simplified purification steps that preclude the need for chromatography.

We report the first examples of catalytic, enantioselective alkylation of N,O-acetals to produce useful amino acid derivatives 5 in high yield (73–93%) and enantioselectivity (70–96%). We have extended the utility of our reaction to include a simple one-pot procedure from readily available starting materials. We also provide several different N-based protecting groups that greatly increase the flexibility of the reaction. In addition, we have elucidated novel mechanistic information including the discovery of unique transilylations that start off the catalytic reactions of enol silane nucleophiles with N,O-acetals. These details will guide us in further explorations of the reaction's scope and utility.

[reaction: see text] The alcohol-catalyzed Diels-Alder reactions of acrolein and benzaldehyde with Rawal's diene were evaluated with density functional theory (B3LYP/6-31G(d)). Several potential modes of catalysis with two methanol molecules were used to model catalysis by TADDOLs. In agreement with crystallographic data, cooperative catalysis with TADDOLs is predicted to be favorable.

The origin of enantioselectivity in the [Cu(R,R)-Ph-box](OTf)2-catalyzed intramolecular aminooxygenation of N-sulfonyl-2-allylanilines and 4-pentenylsulfonamides to afford chiral indolines and pyrrolidines, respectively, was investigated using Density Functional Theory (DFT) calculations. The pyrrolidine-forming transition state model for the major enantiomer involves a chair-like seven-membered cyclization transition state with a distorted square planar copper center, while the transition state model for the minor enantiomer was found to have a boat-like cyclization geometry having a distorted tetrahedral geometry about the copper center. Similar copper-geometry trends were observed in the chiral indoline-forming reactions. These models were found to be qualitatively consistent with experimental results and allowed for rationalization of how substitution of the substrate backbone and N sulfonyl substituent affected the level of enantioselectivity in these and related copper(II)-catalyzed enantioselective reactions.

A Ag(I)-catalyzed synthesis of chiral C(3)-substituted phthalides (8a–f) via a Sakurai–Hosomi allylation/transesterification reaction is described (ee ≤86%). A notable feature of this reaction is that it utilizes ortho-substituted aldehydes, which are a class of compounds that generally afford poor levels of stereoinduction when applying most known catalytic asymmetric allylation approaches. It was also found that elongation of the n-alkyl chain length (R1, up to n=6; R2=H) of the starting alkyl 2-formylbenzoates (7g–i) improved the enantiomeric excess (ee) of the product.

A Lewis acid complex between benzaldehyde and the silver catalyst was detected by (31)P NMR and shown to be the direct precursor to allylation within the Sakurai-Hosomi-Yamamoto reaction. Structural and thermochemical hybrid-DFT calculations indicated that benzaldehyde predominantly formed an η(1)-σ-complex with the catalyst; however, two other competing conformers involving different coordination modes were found, including an activated μ(2)-bound complex. The differences in (31)P NMR shifts upon complexation were calculated by the gauge-independent atomic orbital (GIAO-DFT) method for each conformer. The minimum energy conformer was found to correlate well with chemical shift trends observed experimentally, and an analysis of Mullikan charge populations revealed that the carbonyl carbon of the highest-energy conformer was the most electron-deficient. Furthermore, one minor and three major silicon intermediates were detected by (29)Si NMR and, with the aid of (1)H-(29)Si HSQC, were assigned by comparison with parent compounds and GIAO-DFT calculations. Finally, a tentative mechanism was proposed based on these findings.

A one-pot synthesis of chiral C(3)-substituted phthalides via an indium-mediated allylation/transesterification reaction is described. The development of this reaction was facilitated through the applied use of DFT calculations to rationalize the stereoselection of a chiral In-mediated process. It was discovered that the enantiomeric excess of this reaction depended upon the steric size, chain length, and substitution of the aldehyde employed.

A sequential (R)-BINAP·AgIF (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) (6–10 mol %), and (Ph3P)2PdIICl2 (bis(triphenylphosphine)palladium(II) dichloride) (2 mol %) catalyzed asymmetric Sakurai–Hosomi–Yamamoto allylation/Mizoroki–Heck reaction that affords C1-chiral 3-methylene-indan-1-ols with enantiomeric excess (ee) up to 80% is reported. Notably, this protocol allows for the use of various o-substituted benzaldehydes and allyltrimethoxysilane. It was also discovered that the presence of electron-rich groups had no effect on the enantioselectivity of the reaction, whereas electron-withdrawing groups lead to erosion in product ee.

The trifunctional catalytic system allows efficient and highly enantioselective α-fluorination of a wide range of acid chlorides.