Organocatalytic Route Research Articles

An Organocatalytic Route to endo‐Vinylene Carbonates from Carbon Dioxide‐Based exo‐Vinylene Carbonates

AbstractAn organocatalytic route has been developed for the isomerization of exo‐vinylene carbonates (exo‐VCs) to endo‐vinylene carbonates (endo‐VCs). The exo‐VC starting material can easily be obtained from propargylic alcohols via cyclization with carbon dioxide. In this study, these exo‐VCs are shown to isomerize to the thermodynamically more stable endo‐VCs in the presence of an N‐heterocyclic base and phenol. Density functional theory (DFT) studies were conducted to elucidate the mechanism, tackling difficulties of the description of charge separation steps. This isomerization process delivers an ample diversity of endo‐VCs in good to excellent yields and chemoselectivities under mild reaction conditions.

Organocatalytic Access to a cis-Cyclopentyl-γ-amino Acid: An Intriguing Model of Selectivity and Formation of a Stable 10/12-Helix from the Corresponding γ/α-Peptide.

In this study, we have developed a highly enantioselective organocatalytic route to the (1S,2R)-2-(aminomethyl)cyclopentane-1-carboxylic acid monomer precursor, which has a cis-configuration between the C- and N-termini around the cyclopentane core. Kinetic measurements show that the product distribution changes over time due to epimerization of the C1 center. Computations suggest the cis-selectivity is a result of selective C-C bond formation, while subsequent steps appear to influence the selectivity at higher temperature. The resulting γ-amino acid residue was incorporated into a novel γ/α-peptide, which forms a well-ordered 10/12-helix with alternate H-bond directionality in spite of the smallest value of the ζ-angle yet observed for a helix of this type. This highly defined structure is also a result of the narrow range of potential ζ-angles in our monomer. In contrast, the larger range of potential ζ-values observed for the corresponding trans-system can be fulfilled by several competing helical structures.

Chemical and Biochemical Approaches for the Synthesis of Substituted Dihydroxybutanones and Di- and Tri-Hydroxypentanones.

Polyhydroxylated compounds are building blocks for the synthesis of carbohydrates and other natural products. Their synthesis is mainly achieved by different synthetic versions of aldol-coupling reactions, catalyzed either by organocatalysts, enzymes, or metal-organic catalysts. We have investigated the formation of 1,4-substituted 2,3-dihydroxybutan-1-one derivatives from para- and meta-substituted phenylacetaldehydes by three distinctly different strategies. The first involved a direct aldol reaction with hydroxyacetone, dihydroxyacetone, or 2-hydroxyacetophenone, catalyzed by the cinchona derivative cinchonine. The second was reductive cross-coupling with methyl- or phenylglyoxal promoted by SmI2, resulting in either 5-substituted 3,4-dihydroxypentan-2-ones or 1,4 bis-phenyl-substituted butanones, respectively. Finally, in the third case, aldolase catalysis was employed for synthesis of the corresponding 1,3,4-trihydroxylated pentan-2-one derivatives. The organocatalytic route with cinchonine generated distereomerically enriched syn-products (de = 60-99%), with moderate enantiomeric excesses (ee = 43-56%) but did not produce aldols with either hydroxyacetone or dihydroxyacetone as donor ketones. The SmI2-promoted reductive cross-coupling generated product mixtures with diastereomeric and enantiomeric ratios close to unity. This route allowed for the production of both 1-methyl- and 1-phenyl-substituted 2,3-dihydroxybutanones at yields between 40-60%. Finally, the biocatalytic approach resulted in enantiopure syn-(3 R,4 S) 1,3,4-trihydroxypentan-2-ones.

High-Amylose Maize, Potato, and Butyrylated Starch Modulate Large Intestinal Fermentation, Microbial Composition, and Oncogenic miRNA Expression in Rats Fed A High-Protein Meat Diet.

High red meat intake is associated with the risk of colorectal cancer (CRC), whereas dietary fibers, such as resistant starch (RS) seemed to protect against CRC. The aim of this study was to determine whether high-amylose potato starch (HAPS), high-amylose maize starch (HAMS), and butyrylated high-amylose maize starch (HAMSB)—produced by an organocatalytic route—could oppose the negative effects of a high-protein meat diet (HPM), in terms of fermentation pattern, cecal microbial composition, and colonic biomarkers of CRC. Rats were fed a HPM diet or an HPM diet where 10% of the maize starch was substituted with either HAPS, HAMS, or HAMSB, for 4 weeks. Feces, cecum digesta, and colonic tissue were obtained for biochemical, microbial, gene expression (oncogenic microRNA), and immuno-histochemical (O6-methyl-2-deoxyguanosine (O6MeG) adduct) analysis. The HAMS and HAMSB diets shifted the fecal fermentation pattern from protein towards carbohydrate metabolism. The HAMSB diet also substantially increased fecal butyrate concentration and the pool, compared with the other diets. All three RS treatments altered the cecal microbial composition in a diet specific manner. HAPS and HAMSB showed CRC preventive effects, based on the reduced colonic oncogenic miR17-92 cluster miRNA expression, but there was no significant diet-induced differences in the colonic O6MeG adduct levels. Overall, HAMSB consumption showed the most potential for limiting the negative effects of a high-meat diet.

Cover Feature: Unprecedented Mechanism of an Organocatalytic Route to Conjugated Enynes with a Junction to Cyclic Nitronates (Eur. J. Org. Chem. 2‐3/2019)

The Cover Feature shows a machine that generates conjugated enynes and cyclic nitronates within a one-pot reaction from simple nitroalkenes. The reaction towards both products shares a common pathway that deviates towards enynes or nitronates depending on the reaction conditions. By adjusting additive and base, the selectivity between enynes and nitronates can be controlled. NMR reaction monitoring in combination with theoretical calculations helped to elucidate the mechanism towards both products. This machine stands as a symbol for reaction flasks or NMR-tubes in which the reactions were carried out. More information can be found in the Full Paper by R. M. Gschwind et al.

Unprecedented Mechanism of an Organocatalytic Route to Conjugated Enynes with a Junction to Cyclic Nitronates

Conjugated enynes as well as cyclic nitronates are crucial building blocks for numerous natural products and pharmaceuticals. However, so far, no common and metal‐free synthetic route to both conjugated enynes and cyclic nitronates has been reported. Herein, in situ NMR, labelling studies and theoretical calculations were combined to investigate the mechanism of the unusual triple bond formation towards conjugated enynes. Starting from nitroalkene dimers, first an isoxazolidine‐2,5‐diol derivative is formed as central intermediate. From this, enynes were generated by a combination of oxidation, dehydration, and retro 1,3‐dipolar cycloaddition, whereas for nitronates a base induced intramolecular reorganization is proposed. While the product distribution could be controlled and high yields of nitronate were achieved, only medium to good yields for enynes were obtained due to polymerization losses. Nevertheless, we hope that these mechanistic investigations may provide a basis for further developments of organocatalytic or metal‐free preparations of conjugated enynes and nitronates.

Facile and rapid decarboxylation of glutamic acid to γ-aminobutyric acid via microwave-assisted reaction: Towards valorisation of waste gluten

The growing trend towards the utilisation of biomass to produce fuels and chemicals has the potential to produce large quantities of protein-rich wastes that may be unsuitable for use as a feed. This protein waste could instead serve as a sustainable feedstock for the production of useful nitrogen-containing bio-based chemicals. We report herein the production of γ-aminobutyric acid from glutamic acid via a microwave-assisted decarboxylation reaction using isophorone as an inducer reagent. High yields of 63% can be achieved with only short reaction times (7 min) required. The influences of inducer loading, reaction time and hydrochloric acid concentration used for hydrolysis step of the work up were investigated at different scales. As a proof of concept, glutamic acid was facilely isolated from waste gluten, via microwave assisted hydrolysis, and subsequently decarboxylated with success. To the best of our knowledge this is the first organocatalytic route to γ-aminobutyric acid using glutamic acid as a reagent, and represents an alternative cleaner route to a valuable precursor for bio-based solvents, polymers and pharmaceuticals.

Synthesis of new thioxanthenes by organocatalytic intramolecular Friedel–Crafts reaction

An efficient organocatalytic route has been developed to synthesize novel substituted thioxanthenes (2a–2v) starting from diaryl thioether alcohols (1a–1v) using the intramolecular Friedel–Crafts reaction. The starting materials were obtained in two stages via a coupling reaction followed by the Grignard reaction. In this study, we tried for the first time to use some organic Brønsted acids as organocatalysts (3a–3h) in the intramolecular Friedel–Crafts cyclization reaction of thioether alcohols. The synthesis of original substituted thioxanthenes was achieved within 15 minutes by using N-triflylphosphoramide (3h) with quantitative yields in THF at room temperature.

Highly Active Organic Lewis Pairs for the Copolymerization of Epoxides with Cyclic Anhydrides: Metal-Free Access to Well-Defined Aliphatic Polyesters

Polyester synthesis from the alternating copolymerization of epoxides with cyclic anhydrides via a metal-free route remains a key challenge. This work reports the development of a highly active organocatalytic route for the copolymerization of a spectrum of epoxides and cyclic anhydrides. Fully alternating polyesters were synthesized by a variety of organic Lewis acid–base pairs including organoboranes and quaternary onium salts. The effect of the acidity, type, and size of Lewis pairs on the catalytic activity and selectivity of the copolymerization is presented. The undesirable transesterification and etherification were effectively suppressed even in the case of complete conversion of the cyclic anhydride. This could be ascribed to the formation of a unique tetracoordinate bond-carboxylate (or alkoxide) anion. The Lewis pairs are highly active, with a turnover frequency of 102 and 303 h–1 for the copolymerization of propylene oxide with maleic anhydride and phthalic anhydride, respectively, at 80 °C. B...

Betulin-Constituted Multiblock Amphiphiles for Broad-Spectrum Protein Resistance.

Multiblock-like amphiphilic polyurethanes constituted by poly(ethylene oxide) and biosourced betulin are designed for antifouling and synthesized by a convenient organocatalytic route comprising tandem chain-growth and step-growth polymerizations. The doping density of betulin (DB) in the polymer chain structure is readily varied by a mixed-initiator strategy. The spin-coated polymer films exhibit unique nanophase separation and protein resistance behaviors. Higher DB leads to enhanced surface hydrophobicity and, unexpectedly, improved protein resistance. It is found that the surface holds molecular-level heterogeneity when DB is substantially high due to restricted phase separation; therefore, broad-spectrum protein resistance is achieved despite considerable surface hydrophobicity. As DB decreases, the distance between adjacent betulin units increases so that hydrophobic nanodomains are formed, which provide enough landing areas for relatively small-sized proteins to adsorb on the surface.

Retraction of "Access to Cyclobutadienes via an Organocatalytic Dienamine-Iminium-Allenamine Cascade Approach".

A new organocatalytic route to cyclobutadienes from α,β-unsaturated aldehydes and ynals is described. This protocol allows a broad substrate scope and mild conditions. Furthermore, a proposed mechanism of a dienamine–iminium–allenamine cascade process is discussed.

Access to Cyclobutadienes via an Organocatalytic Dienamine-Iminium-Allenamine Cascade Approach.

A new organocatalytic route to cyclobutadienes from α,β-unsaturated aldehydes and ynals is described. This protocol allows a broad substrate scope and mild conditions. Furthermore, a proposed mechanism of a dienamine-iminium-allenamine cascade process is discussed.

Total Synthesis of (–)-Herbaric Acid through Organocatalyzed Asymmetric Halolactonization of Acrylate-Type Benzoic Acids

The total synthesis of (–)-herbaric acid has been achieved through the stereoselective synthesis of 3-substituted isobenzofuranones with a new organocatalytic route. When combined with a catalytic amount of benzoic acid, quinidine thiocarbamate based bifunctional catalysts have demonstrated their efficiency for the diastereoselective halolactonization reaction of acrylate-type benzoic acids bearing a chiral alkoxycarbonyl group on the carbon–carbon double bond. High diastereomeric excesses were obtained thanks to a positive match effect between the (+)-menthyl ester group and the chiral organocatalyst.

Diastereoselective synthesis of furanose and pyranose substituted glycine and alanine derivatives via proline-catalyzed asymmetric α-amination of aldehydes

A concise organocatalytic route toward the synthesis of furanose and pyranose substituted glycine and alanine derivatives is reported. These compounds are core structural units of some of the naturally available antibiotics and antifungal agents. Proline-catalyzed asymmetric α-amination of aldehydes derived from sugars is used as the key reaction to synthesize twelve sugar amino acid derivatives. The asymmetric transformations proceeded in good yields and with good to excellent diastereoselectivity. The application of the synthesized amino acids is demonstrated by synthesizing a tripeptide containing one of them.

Organocatalyst-Induced Multicomponent Reaction: An Efficient Procedure for the Activation of Amides

An efficient organocatalytic route for the activation of amide derivatives is reported. In this transformation, amide derivatives were employed as a potential bidentate nucleophile in a reaction involving isoquinoline and propiolates using tetrabutylphosphonium acetate to form 1,2-dihydroisoquinoline skeletons.

Organocatalytic route to enantioselective synthesis of ceramide trafficking inhibitor HPA-12

A new organocatalytic approach to the synthesis of ceramide trafficking inhibitor HPA-12 has been described starting from phenacyl bromide. The strategy involves chiral CBS reduction of γ-ketoester and proline-catalyzed α-amination reaction of aldehyde followed by reduction as the key chirality inducing steps.

Clickable Polylactic Acids by Fast Organocatalytic Ring-Opening Polymerization in Continuous Flow

The use of microreactor technology for the ring-opening polymerization of l-lactide catalyzed by 1,5,7-triazabicyclo[4.4.0]dec-5-ene allows for rapid optimization of reaction parameters (reaction temperature and residence time). At moderate catalyst loading, good control over the polymerization is demonstrated by high conversion of monomer (>95%) and low polydispersity (<1.3) at residence times as low as 2 s. This metal-free, organocatalytic route yields well-defined poly(lactic acid) in continuous flow and by using bicyclononyne- and tetrazine-containing initiators gives access to poly(lactic acid) amenable to click chemistry.

Organocatalytic route for the synthesis of propionylated starch

In recent years acetylated, propionylated and butyrylated starches have received special attention due to their capacity to deliver specific short chain fatty acids (SCFAs) to the colon in a sustained and predictable manner, and thus contribute to maintaining the normal physiologic function of the large bowel and preventing specific diseases.In the current contribution a non-conventional organocatalytic solventless route for the eco-friendly propionylation of corn starch is proposed. The catalyst used in the acylation is a naturally occurring α-hydroxy acid (l-tartaric acid). Propionylated starches with degree of substitution (DS) in the 0.05–1.59 interval were obtained and characterized in terms of chemical structure, morphology, crystallinity, thermal stability and hydrophilicity. Results showed that by the proposed methodology propionylated starch with the DS required for clinical use (i.e. 0.2–0.3) could be obtained within 2–3h of reaction. Characterization results evidenced the progressive loss of crystallinity of starch granules as higher substitution levels were conferred.

An efficient organocatalytic route for asymmetric total synthesis of Stagonolide F

A stereoselective total synthesis of Stagonolide F (98% ee) is described employing asymmetric α-aminooxylation, Jorgensen’s asymmetric epoxidation, Brown asymmetric allylation, Steglich esterification and ring closing metathesis as key steps. The use of organocatalytic α-aminooxylation and Jorgensen’s asymmetric epoxidation of aldehydes for the introduction of chirality makes this approach more attractive.

Organocatalytic and scalable synthesis of the anti-influenza drugs zanamivir, laninamivir, and CS-8958.

Zanamivir, laninamivir, and CS-8958 are three neuraminidase inhibitors that have been clinically used to combat influenza. We report herein a novel organocatalytic route for preparing these agents. Only 13 steps are needed for the assembly of zanamivir and laninamivir from inexpensive D-araboascorbic acid by this synthetic route, which relies heavily on a thiourea-catalyzed enantioselective Michael addition of acetone to tert-butyl (2-nitrovinyl)carbamate and an anti-selective Henry reaction of the resulting Michael adduct with an aldehyde prepared from D-araboascorbic acid. The synthetic procedures are scalable, as evident from the preparation of more than 3.5 g of zanamivir.