Adding a Hydrogen Bond May Not Help: Naphthyridinone vs Quinoline Inhibitors of Macrophage Migration Inhibitory Factor.

Coordination of the ammonium group of Lys32 in the active site of human macrophage migration inhibitory factor (MIF) using a 1,7-naphthyridin-8-one instead of a quinoline is investigated. Both gas- and aqueous-phase DFT calculations for model systems indicate potential benefits for the added hydrogen bond with the lactam carbonyl group, while FEP results are neutral. Three crystal structures are reported for complexes of MIF with 3a, 4a, and 4b, which show that the desired hydrogen bond is formed with O-N distances of 2.8-3.0 Å. Compound 4b is the most potent new MIF inhibitor with Ki and Kd values of 90 and 94 nM; it also has excellent aqueous solubility, 288 µg/mL. Consistent with the FEP results, the naphthyridinones are found to have similar potency as related quinolines in spite of the additional protein-ligand hydrogen bond.

Design, synthesis, and protein crystallography of biaryltriazoles as potent tautomerase inhibitors of macrophage migration inhibitory factor.

Optimization is reported for biaryltriazoles as inhibitors of the tautomerase activity of human macrophage migration inhibitory factor (MIF), a proinflammatory cytokine associated with numerous inflammatory diseases and cancer. A combined approach was taken featuring organic synthesis, enzymatic assaying, crystallography, and modeling including free-energy perturbation (FEP) calculations. X-ray crystal structures for 3a and 3b bound to MIF are reported and provided a basis for the modeling efforts. The accommodation of the inhibitors in the binding site is striking with multiple hydrogen bonds and aryl-aryl interactions. Additional modeling encouraged pursuit of 5-phenoxyquinolinyl analogues, which led to the very potent compound 3s. Activity was further enhanced by addition of a fluorine atom adjacent to the phenolic hydroxyl group as in 3w, 3z, 3aa, and 3bb to strengthen a key hydrogen bond. It is also shown that physical properties of the compounds can be modulated by variation of solvent-exposed substituents. Several of the compounds are likely the most potent known MIF tautomerase inhibitors; the most active ones are more than 1000-fold more active than the well-studied (R)-ISO-1 and more than 200-fold more active than the chromen-4-one Orita-13.

Abiotic synthesis of amino acids and self-crystallization under prebiotic conditions.

Building on previous research on the origin and homochirality of life, this study focuses on analyses profiling important building blocks of life: the natural amino acids. The spark discharge variation of the iconic Miller experiment was performed with a reducing gas mixture of ammonia, methane, water and hydrogen. Amino acid analysis using liquid chromatography coupled with tandem mass spectrometry after pre-column derivatizaiton revealed the generation of several amino acids including those essential for life. Re-crystallization of the synthetic products and enantiomeric ratio analysis were subsequently performed. Results from liquid chromatography coupled with either fluorescent detector or tandem mass spectrometry after pre-column derivatization with chiral reagent revealed spontaneous and effective asymmetric resolution of serine and alanine. This work describes a useful analytical platform for investigation of hypotheses regarding the origin and homochirality of amino acids under prebiotic conditions. The formation of numerous amino acids in the electric discharge experiment and the occurrence of high enantiomeric ratios of amino acids in re-crystallization experiment give valuable implications for future studies in unraveling fundamental questions regarding origins and evolution of life.

Catalytic enantioselective ß-alkylation of α,ß-unsaturated aldehydes by combination of transition-metal- and aminocatalysis: total synthesis of bisabolane sesquiterpenes.

Branching out! The first co-catalytic enantioselective (up to 98:2 e.r.) ß-alkylation of α,ß-unsaturated aldehydes by combination of simple chiral amine and copper catalysts provides ß-branched aldehydes in a one-pot protocol. The methodology was applied to the short total syntheses of bisabolane sesquiterpenes (S)-(+)-curcumene, (E)-(S)-(+)-3-dehydrocurcumene and (S)-(+)-tumerone.

Catalytic asymmetric aziridination of α,ß-unsaturated aldehydes.

The development, scope, and application of the highly enantioselective organocatalytic aziridination of α,ß-unsaturated aldehydes is presented. The aminocatalytic azirdination of α,ß-unsaturated aldehydes enables the asymmetric formation of ß-formyl aziridines with up to >19:1 d.r. and 99% ee. The aminocatalytic aziridination of α-monosubstituted enals gives access to terminal α-substituted-α-formyl aziridines in high yields and up to 99% ee. In the case of the organocatalytic aziridination of disubstituted α,ß-unsaturated aldehydes, the transformations were highly diastereo- and enantioselective and give nearly enantiomerically pure ß-formyl-functionalized aziridine products (99% ee). A highly enantioselective one-pot cascade sequence based on the combination of asymmetric amine and N-heterocyclic carbene catalysis (AHCC) is also disclosed. This one-pot three-component co-catalytic transformation between α,ß-unsaturated aldehydes, hydroxylamine derivatives, and alcohols gives the corresponding N-tert-butoxycarbonyl and N-carbobenzyloxy-protected ß-amino acid esters with ee values ranging from 92-99%. The mechanisms and stereochemistry of all these catalytic transformations are also discussed.

Inorganic ammonium salts and carbonate salts are efficient catalysts for aldol condensation in atmospheric aerosols.

In natural environments such as atmospheric aerosols, organic compounds coexist with inorganic salts but, until recently, were not thought to interact chemically. We have recently shown that inorganic ammonium ions, NH(4)(+), act as catalysts for acetal formation from glyoxal, a common atmospheric gas. In this work, we report that inorganic ammonium ions, NH(4)(+), and carbonate ions, CO(3)(2-), are also efficient catalysts for the aldol condensation of carbonyl compounds. In the case of NH(4)(+) this was not previously known, and was patented prior to this article. The kinetic results presented in this work show that, for the concentrations of ammonium and carbonate ions present in tropospheric aerosols, the aldol condensation of acetaldehyde and acetone could be as fast as in concentrated sulfuric acid and might compete with their reactions with OH radicals. These catalytic processes could produce significant amounts of polyconjugated, light-absorbing compounds in aerosols, and thus affect their direct forcing on climate. For organic gases with large Henry's law coefficients, these reactions could also result in a significant uptake and in the formation of secondary organic aerosols (SOA). This work reinforces the recent findings that inorganic salts are not inert towards organic compounds in aerosols and shows, in particular, that common ones, such as ammonium and carbonate salts, might even play important roles in their chemical transformations.

Dynamic kinetic asymmetric transformation (DYKAT) by combined amine- and transition-metal-catalyzed enantioselective cycloisomerization.

The first examples of one-pot highly chemo- and enantioselective dynamic kinetic asymmetric transformations (DYKATs) involving alpha,beta-unsaturated aldehydes and propargylated carbon acids are presented. These DYKATs, which proceed by a combination of catalytic iminium activation, enamine activation, and Pd(0)-catalyzed enyne cycloisomerization, give access to functionalized cyclopentenes with up to 99 % ee and can be used for the generation of all-carbon quaternary stereocenters.

Highly enantioselective organocatalytic addition of aldehydes to N-(Phenylmethylene)benzamides: asymmetric synthesis of the paclitaxel side chain and its analogues.

Easily side-tracked: A simple route to the paclitaxel side chain and its analogues is based on the (R)-proline-catalyzed addition of aldehydes to N-(phenylmethylene)benzamides, followed by oxidation of the resulting protected alpha-hydroxy-beta-benzoylaminoaldehydes (92-99 % ee). Esterification of the subsequent phenylisoserine derivatives with baccatin III gives paclitaxel analogues (see scheme).A simple highly enantioselective organocatalytic addition of aldehydes to N-(phenylmethylene)benzamides is presented. The application of (R)-proline as the catalyst and subsequent oxidation of the protected alpha-hydroxy-beta-benzoylaminoaldehydes (92-99 % ee) gives access to esterification-ready phenylisoserine derivatives such as the protected paclitaxel (taxol) side chain. Esterification of these derivatives with baccatin III gives access to the cancer chemotherapeutic substance paclitaxel and its analogues that do not exist in nature.

Products and kinetics of the liquid-phase reaction of glyoxal catalyzed by ammonium ions (NH4(+)).

Glyoxal, a common atmospheric gas, has been reported to be depleted in some regions of the atmosphere. The corresponding sink could be accounted for by reactions in or at the surface of atmospheric particles, but these reactions were not identified. Recently, we showed that inorganic ammonium ions, NH(4)(+), are efficient catalysts for reactions of carbonyl compounds, including glyoxal, in the liquid phase. To determine whether ammonium-catalyzed reactions can contribute to depletion of glyoxal in the atmosphere, the reactivity of this compound in aqueous solutions containing ammonium salts (ammonium sulfate, chloride, fluoride, and phosphate) at 298 K has been studied. The products identified by LC-HRMS and UV absorption revealed a mechanism involving two distinct pathways: a Bronsted acid pathway and an iminium pathway. The kinetics of the iminium pathway was studied by monitoring formation of a specific product. This pathway was second order in glyoxal in most of the solutions studied and should therefore be second order in most ammonium-containing aerosols in the atmosphere. The corresponding rate constant, k(II) (M(-1) s(-1)), increased strongly with ammonium ion activity, a(NH(4)(+)), and pH: k(II) (M(-1) s(-1)) = (2 +/- 1) x 10(-10) exp((1.5 +/- 0.8)aNH(4)(+)) exp((2.5 +/- 0.2)pH). This iminium pathway is a lower limit for the ammonium-catalyzed consumption of glyoxal, but the contribution of the acid pathway is expected to be small in tropospheric aerosols. With these results the reactive uptake of glyoxal on ammonium-containing aerosols was estimated and shown to be a possible explanation for depletion of this compound in Mexico City.

One-pot catalytic enantioselective domino nitro-michael/michael synthesis of cyclopentanes with four stereocenters.

A highly enantioselective organocatalytic one-pot synthesis of nitro-, formyl-, and ester-functionalized cyclopentanes with four stereocenters is presented. The cyclopentanes were formed as a predominant diasteroisomer and isolated in high yields with 97-99 % ee.

One-pot organocatalytic domino Michael/alpha-alkylation reactions: direct catalytic enantioselective cyclopropanation and cyclopentanation reactions.

The development of one-pot organocatalytic domino Michael/alpha-alkylation reactions between bromomalonates or bromoacetoacetate esters and alpha,beta-unsaturated aldehydes is presented. The chiral-amine-catalyzed reactions with bromomalonates as substrates give access to the corresponding 2-formylcyclopropane derivatives in high yields with excellent diastereoselectivity and up to 99 % ee. The catalytic domino Michael/alpha-alkylation reactions between 4-bromo-acetoacetate and enals provide a route for the synthesis of functionalized cyclopentanones in good to high yields with 93-99 % ee. The products from the organocatalytic reactions were also reduced with high diastereoselectivity to the corresponding cyclopropanols and cyclopentanols, respectively. Moreover, one-pot combinations of amine and heterocyclic carbene catalysis (AHCC) enabled the highly enantioselective synthesis of beta-malonate esters (91-97 % ee) from the reaction between bromomalonates and enals. The tandem catalysis included the catalytic domino reaction followed by catalytic in situ chemoselective ring-opening of the 2-formylcyclopropane intermediates.

Direct asymmetric intermolecular aldol reactions catalyzed by amino acids and small peptides.

In nature there are at least nineteen different acyclic amino acids that act as the building blocks of polypeptides and proteins with different functions. Here we report that alpha-amino acids, beta-amino acids, and chiral amines containing primary amine functions catalyze direct asymmetric intermolecular aldol reactions with high enantioselectivities. Moreover, the amino acids can be combined into highly modular natural and unusual small peptides that also catalyze direct asymmetric intermolecular aldol reactions with high stereoselectivities, to furnish the corresponding aldol products with up to >99 % ee. Simple amino acids and small peptides can thus catalyze asymmetric aldol reactions with stereoselectivities matching those of natural enzymes that have evolved over billions of years. A small amount of water accelerates the asymmetric aldol reactions catalyzed by amino acids and small peptides, and also increases their stereoselectivities. Notably, small peptides and amino acid tetrazoles were able to catalyze direct asymmetric aldol reactions with high enantioselectivities in water, while the parent amino acids, in stark contrast, furnished nearly racemic products. These results suggest that the prebiotic oligomerization of amino acids to peptides may plausibly have been a link in the evolution of the homochirality of sugars. The mechanism and stereochemistry of the reactions are also discussed.

The small peptide-catalyzed direct asymmetric aldol reaction in water.

Simple modular di- and tripeptides with a primary amine at the N-terminus catalyze the aqueous asymmetric aldol reaction between unmodified ketones and aldehydes to furnish the corresponding beta-hydroxy ketones with up to 86% ee in water and 99% ee in aqueous media.

Small peptides as modular catalysts for the direct asymmetric aldol reaction: ancient peptides with aldolase enzyme activity.

Simple peptides and their analogues having a primary amino group as the catalytic residue mediate the direct asymmetric intermolecular aldol reaction with high stereoselectivity and furnish the corresponding aldol products with up to 99% ee; this intrinsic ability of highly modular peptides may explain the initial molecular evolution of aldolase enzymes.