Hydrogen-bonding Catalysis Research Articles

Catalytic Enantioselective [2+2] Intermolecular Photocycloaddition

Key words hydrogen-bonding catalysis - [2+2] photocyclo-addition - photochemistry - photosensitizer

The influencing mechanism of acidity on the oxidation peak currents of guanine and uric acid: hydrogen bond catalysis and degree of auxiliary electrode reduction reaction

In this paper, a pre-anodized inlaying ultrathin carbon paste electrode with 316L stainless steel as a matrix (316L-PAIUCPE) was constructed by a simple and fast electrochemical method. Taking uric acid (UA) and guanine (G) as the target compounds, it was discussed in detail to illustrate the dependent of the peak currents intensity of (ip) of UA and G upon the pH on the basis of the charge properties of the electrode surface active groups, the formation and catalysis of hydrogen bond, the molecular configuration of target, the degree of oxygen reduction reaction at the auxiliary electrode, the oxidation peak potential, distribution coefficient of both UA and G, and so on. A new mechanism was proposed that decreasing of the ip of UA and G with the increasing of pH might result from the degree of oxygen reduction reaction at the auxiliary electrode, although the oxidation peak potential shifted negatively. Moreover, In pH=5.00 phosphate buffer solution, a linear relationship between oxidation peak current and concentration of UA and G was obtained in the range of 5.0×10−7 to 2.2×10−4 mol·L−1 and 2.0×10−7 to 1.5×10−4 mol·L−1 with a detection limit of 8.2×10−8 and 3.4×10−8 mol·L−1, respectively. The constructed electrode exhibited excellent reproducibility and stability. Finally, this technique was employed for simultaneous determination of UA and G in human urine with satisfactory results.

A Cooperative Hydrogen‐Bond‐Promoted Organophotoredox Catalysis Strategy for Highly Diastereoselective, Reductive Enone Cyclization

This new method gives trans-1,2-cycloalkanes and heterocycles providing the first example of combining photoredox approach with hydrogen-bond catalysis.

Urea Metal–Organic Frameworks as Effective and Size-Selective Hydrogen-Bond Catalysts

A new urea-containing metal-organic framework (MOF) was synthesized to act as a heterogeneous catalyst. Ureas are well-known for self-recognition and aggregation behavior, resulting in loss of catalytic competency. The catalyst spatial isolation achievable in a porous MOF environment suggests a potentially general solution. The combination of a symmetrical urea tetracarboxylate strut, 4,4'-bipyridine, and Zn(NO(3))(2)·6H(2)O under solvothermal conditions afforded a new microporous MOF (NU-601). This material is indeed an effective hydrogen-bond-donor catalyst for Friedel-Crafts reactions between pyrroles and nitroalkenes, whereas a homogeneous urea is much less competent. The higher rates of reaction of small substrates relative to larger ones with NU-601 strongly suggest that catalysis primarily occurs within the pores of this new material rather than on its exterior. To the best of our knowledge, this approach is the first example of specific engineering of successful hydrogen-bonding catalysis into a MOF material.

Asymmetric Organocatalytic Formal [2 + 2]-Cycloadditions via Bifunctional H-Bond Directing Dienamine Catalysis

A new concept in organocatalysis allowing for the construction of cyclobutanes with four contiguous stereocenters with complete diastereo- and enantiomeric control by a formal [2 + 2]-cycloaddition is presented. The concept is based on simultaneous dual activation of α,β-unsaturated aldehydes and nitroolefins by amino- and hydrogen-bonding catalysis, respectively. A new bifunctional squaramide-based aminocatalyst has been designed and synthesized in order to enable such an activation strategy. The potential and scope of the reaction are demonstrated, and computational studies which account for the stereochemical outcome are presented.

Highly Efficient Hydrogen-Bonding Catalysis of the Diels–Alder Reaction of 3-Vinylindoles and Methyleneindolinones Provides Carbazolespirooxindole Skeletons

Carbazolespirooxindole derivatives were synthesized in a high-yielding, atypically rapid, stereocontrolled Diels-Alder reaction catalyzed by a C(2)-symmetric bisthiourea organocatalyst. Simple precursors and mild conditions were used to construct carbazolespirooxindole derivatives with high enantiopurity and structural diversity under H-bonding catalysis. The practical approach recycles the organocatalyst and solvent. This simple and efficient operational procedure will allow diversity-oriented syntheses of this intriguing class of compounds.

Racemase Activity of B. cepacia Lipase Leads to Dual‐Function Asymmetric Dynamic Kinetic Resolution of α‐Aminonitriles

The Diels-Alder reaction is one of the most powerful synthetic tools in organic chemistry, and asymmetric Diels-Alder catalysis allows for rapid construction of chiral carbon scaffolds. For this reason, considerable effort has been invested in developing efficient and stereoselective organo- and biocatalysts. However, Diels-Alder is a virtually unknown reaction in Nature, and to engineer an enzyme into a Diels-Alderase is therefore a challenging task. Despite several successful designs of catalytic antibodies since the 1980’s, their catalytic activities have remained low, and no true artificial ’Diels-Alderase’ enzyme was reported before 2010.In this thesis, we employ state-of-the-art computational tools to study the mechanism of organocatalyzed Diels-Alder in detail, and to redesign existing enzymes into intermolecular Diels-Alder catalysts. Papers I–IV explore the mechanistic variations when employing increasingly activated reactants and the effect of catalysis. In particular, the relation between the traditionally presumed concerted mechanism and a stepwise pathway, forming one bond at a time, is probed. Papers V–X deal with enzyme design and the computational aspects of predicting catalytic activity. Four novel, computationally designed Diels-Alderase candidates are presented in Papers VI–IX. In Paper X, a new parameterization of the Linear Interaction Energy model for predicting protein-ligand affinities is presented.A general finding in this thesis is that it is difficult to attain large transition state stabilization effects solely by hydrogen bond catalysis. In addition, water (the preferred solvent of enzymes) is well-known for catalyzing Diels- Alder by itself. Therefore, an efficient Diels-Alderase must rely on large binding affinities for the two substrates and preferential binding conformations close to the transition state geometry. In Papers VI–VIII, we co-designed the enzyme active site and substrates in order to achieve the best possible complementarity and maximize binding affinity and pre-organization. Even so, catalysis is limited by the maximum possible stabilization offered by hydrogen bonds, and by the inherently large energy barrier associated with the [4+2] cycloaddition.The stepwise Diels-Alder pathway, proceeding via a zwitterionic intermediate, may offer a productive alternative for enzyme catalysis, since an enzyme active site may be more differentiated towards stabilizing the high-energy states than for the standard mechanism. In Papers I and III, it is demonstrated that a hydrogen bond donor catalyst provides more stabilization of transition states having pronounced charge-transfer character, which shifts the preference towards a stepwise mechanism.Another alternative, explored in Paper IX, is to use an α,β -unsaturated ketone as a ’pro-diene’, and let the enzyme generate the diene in situ by general acid/base catalysis. The results show that the potential reduction in the reaction barrier with such a mechanism is much larger than for conventional Diels-Alder. Moreover, an acid/base-mediated pathway is a better mimic of how natural enzymes function, since remarkably few catalyze their reactions solely by non-covalent interactions.

A higher energy conformer of ( S)-proline is the active catalyst in intermolecular aldol reaction: Evidence from DFT calculations

Full catalytic cycle of the stereoselective ( S)-proline catalyzed aldol reaction of acetone and acetaldehyde in DMSO solvent has been investigated using three different DFT methods, viz. B3LYP, MPWB1K and B97D in conjunction with the polarizable continuum (PCM) method. At all the levels of theory, one of the higher energy conformers of the catalyst, 1b showed higher activity than the most stable conformer, 1a. On the basis of Δ G # of 39.8 kcal/mol observed for the reaction of 1a with acetone, 1a is considered to be inactive in the catalytic cycle while the same reaction with 1b showed 22.7 kcal/mol (B97D-PCM level) lower value for Δ G # than 1a. All the possibilities for enamine formation and C–C bond formation step have been considered for describing the most appropriate stereoselective catalytic cycle which showed that the full cycle is made up of a relay of eight proton transfer steps and the reaction is categorized under hydrogen bond catalysis. The hydration across the iminium bond of the second nucleophilic adduct – an intermediate formed subsequent to the aldehyde addition to the enamine – is the rate limiting step of the reaction with Δ G # = 21.7 kcal/mol (B97D-PCM level).

Highly Efficient Hydrogen-Bond Catalysis with (Thio)Phosphorodiamides

Highly Efficient Hydrogen-Bond Catalysis with (Thio)Phosphorodiamides

Hydrogen-Bonding Catalysis and Inhibition by Simple Solvents in the Stereoselective Kinetic Epoxide-Opening Spirocyclization of Glycal Epoxides to Form Spiroketals

Mechanistic investigations of a MeOH-induced kinetic epoxide-opening spirocyclization of glycal epoxides have revealed dramatic, specific roles for simple solvents in hydrogen-bonding catalysis of this reaction to form spiroketal products stereoselectively with inversion of configuration at the anomeric carbon. A series of electronically tuned C1-aryl glycal epoxides was used to study the mechanism of this reaction based on differential reaction rates and inherent preferences for S(N)2 versus S(N)1 reaction manifolds. Hammett analysis of reaction kinetics with these substrates is consistent with an S(N)2 or S(N)2-like mechanism (ρ = -1.3 vs ρ = -5.1 for corresponding S(N)1 reactions of these substrates). Notably, the spirocyclization reaction is second-order dependent on MeOH, and the glycal ring oxygen is required for second-order MeOH catalysis. However, acetone cosolvent is a first-order inhibitor of the reaction. A transition state consistent with the experimental data is proposed in which one equivalent of MeOH activates the epoxide electrophile via a hydrogen bond while a second equivalent of MeOH chelates the side-chain nucleophile and glycal ring oxygen. A paradoxical previous observation that decreased MeOH concentration leads to increased competing intermolecular methyl glycoside formation is resolved by the finding that this side reaction is only first-order dependent on MeOH. This study highlights the unusual abilities of simple solvents to act as hydrogen-bonding catalysts and inhibitors in epoxide-opening reactions, providing both stereoselectivity and discrimination between competing reaction manifolds. This spirocyclization reaction provides efficient, stereocontrolled access to spiroketals that are key structural motifs in natural products.

Asymmetric organocatalytic reactions by bifunctional amine-thioureas

The development of organocatalysts has greatly changed the art of organic transformation in the chemical synthesis community for the past decades. Nature's work underpins the success of hydrogen-bonding catalysis were obviously shown in a myriad of enzymatic reactions. More recently, the emergence of bifunctional organocatalysts which work complementarily in activating two components of a chemical reaction has emerged as a frontier of research in asymmetric synthesis. In this particular review, works on asymmetric reactions catalyzed by bifunctional amine-thioureas are examined.

Enantioselective Synthesis of Coumarins Catalyzed by a Bifunctional Amine–Thiourea Catalyst

Efficient excess: An efficient and facile enantioselective Michael addition reaction through hydrogen-bonding catalysis for the synthesis of coumarin complexes has been developed (see scheme). A simple bifunctional amine–thiourea small molecule has been discovered to catalyze this process with high yields and high to excellent enantiomeric excesses. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Concise Syntheses of the Abyssinones and Discovery of New Inhibitors of Prostate Cancer and MMP-2 Expression

Hydrogen-bonding catalysis is an emerging field that facilitates rapid access to medicinally relevant enantioenriched small molecules. Here, we report the first asymmetric total syntheses of four members of the abyssinone class of natural products (I, II, III, and IV 4´-OMe) via quinine- or quinidine-derived thiourea-catalyzed intramolecular conjugate additions of β-keto ester alkylidenes. This concise strategy includes a tandem deprotection/decarboxylation final step that delivers all four natural products and their corresponding antipodes. A preliminary evaluation of all of these small molecules against a metastatic human prostate cancer cell line has identified that these compounds selectively and differentially inhibit cell growth and downregulate the expression of matrix metalloproteinase-2 (MMP-2) at non-toxic concentrations.

ChemInform Abstract: Hydrogen Bond Catalysis or Broensted Acid Catalysis? General Considerations

AbstractReview: 40 refs.

ChemInform Abstract: Diastereoselective and Enantioselective Mukaiyama Aldol Reactions of α‐Ketoesters Using Hydrogen Bond Catalysis.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Efficient Phosphite Addition to Nitroalkenes Using Squaramide Catalysis

Having recently introduced the squaramide motif in hydrogen-bonding catalysis (J. Am. Chem. Soc. 2008, 130, 14416), Rawal and colleagues now demonstrate its high efficiency in the Michael addition of diphenyl phosphite to nitroalkenes. Excellent enantiomeric induction and yields were observed for a range of nitroalkene substrates. Aliphatic and aromatic nitroalkenes were found to be equally suitable substrates.

Diastereoselective and enantioselective Mukaiyama aldol reactions of α-ketoesters using hydrogen bond catalysis

Hydrogen bond catalyzed Mukaiyama aldol reactions of alpha-ketoesters proceed in high diastereo- and enantioselectivities, giving products possessing two chiral centers, of which one is a tertiary alcohol.

New architectures in hydrogen bond catalysis

New achiral sulfamide, phosphoric triamide, and thiophosphoric triamide compounds have been synthesized. Their activity as hydrogen bond catalysts for the Friedel–Crafts and Baylis–Hillman reactions compares favorably with that of a known and an active thiourea catalyst. The new compounds were also studied by X-ray crystallography and their solid state structures are described.

A New Organocatalytic Approach to Substituted Unsaturated Lactams

The first organocatalytic approach to erythro and threo lactam derivatives was successfully achieved from the addition of TBSOP (1) to aromatic and aliphatic aldehydes in the presence of a commercially available urea-derivative 5 supporting the broad potential for hydrogen-bond catalysis in the vinylogous Mukaiyama aldol addition. The transition states leading to the major diastereoisomers are discussed.

DFT Studies on Double Hydrogen Bond Catalysis of Reactions of Distinct Polarity

AbstractThe Diels–Alder cycloaddition and the enamine‐aldol reactions catalyzed by double‐site hydrogen‐bond donors were computationally studied at the B3LYP and MP2/6‐311++G** levels. The comparison of bifurcated and cooperative H‐bonding activation of the electrophile in both reactions with 1,3‐propanediol, 1,4‐butanediol, glycolic acid and two molecules of methanol strongly suggests that the activation mode depends on the electronic features of the carbonyl oxygen atom in the H‐bond acceptor. The bifurcated arrangement of the hydrogen‐bond donors is predicted to be favoured as the polarity of the reaction increases. Consequently, the transition states of the Diels–Alder reaction are better stabilized by a cooperative interaction with the diols and those of the more polar enamine‐aldol reaction by a bifurcated interaction. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)