Project description:Herein, we present a novel approach for various asymmetric transformations of cyclic enones. The combination of readily accessible chiral diamines and sterically demanding flexible phosphoric acids resulted in a simple and highly tunable catalyst framework. The careful optimization of the catalyst components led to the identification of a particularly powerful and multi-purpose organocatalyst, which was successfully applied for asymmetric epoxidations, aziridinations, aza-Michael-initiated cyclizations, as well as for a novel Robinson-like Michael-initiated ring closure/aldol cyclization. High catalytic activities and excellent stereocontrol was observed for all four reaction types, indicating the excellent versatility of our catalytic system. Furthermore, a simple change in the diamine's configuration provided easy access to both product antipodes in all cases.
Project description:The development of catalytic enantioselective methods is routinely carried out using easily accessible and prototypical substrates. This approach to reaction development often yields asymmetric methods that perform poorly using substrates that are sterically or electronically dissimilar to those used during the reaction optimization campaign. Consequently, expanding the scope of previously optimized catalytic asymmetric reactions to include more challenging substrates is decidedly nontrivial. Here, we address this challenge through the development of a systematic workflow to broaden the applicability and reliability of asymmetric conjugate additions to substrates conventionally regarded as sterically and electronically demanding. The copper-catalyzed asymmetric conjugate addition of alkylzirconium nucleophiles to form tertiary centers, although successful for linear alkyl chains, fails for more sterically demanding linear α,β-unsaturated ketones. Key to adapting this method to obtain high enantioselectivity was the synthesis of modified phosphoramidite ligands, designed using quantitative structure-selectivity relationships (QSSRs). Iterative rounds of model construction and ligand synthesis were executed in parallel to evaluate the performance of 20 chiral ligands. The copper-catalyzed asymmetric addition is now more broadly applicable, even tolerating linear enones bearing tert-butyl β-substituents. The presence of common functional groups is tolerated in both nucleophiles and electrophiles, giving up to 99% yield and 95% ee across 20 examples.
Project description:A variety of novel imidazolidinone-based organocatalysts with bulky substituents were synthesized under mild reaction conditions starting from easily accessible substrates. Different natural and unnatural amino acid methyl amides were cyclized with aromatic carbaldehydes to yield two diastereomeric MacMillan-type catalysts. Special emphasis was put on bulky residues such as mesityl and pyrene moieties.
Project description:The biocatalytic Friedel-Crafts acylation has been identified recently for the acetylation of resorcinol using activated acetic acid esters for the synthesis of acetophenone derivatives catalyzed by an acyltransferase. Because the wild-type enzyme is limited to acetic and propionic derivatives as the substrate, variants were designed to extend the substrate scope of this enzyme. By rational protein engineering, the key residue in the active site was identified which can be replaced to allow binding of bulkier acyl moieties. The single-point variant F148V enabled the transformation of previously inaccessible medium chain length alkyl and alkoxyalkyl carboxylic esters as donor substrates with up to 99% conversion and up to >99% isolated yield.
Project description:Chiral imidazolium l-prolinate salts, providing a complex network of supramolecular interaction in a chiral environment, have been studied as synzymatic catalytic systems. They are demonstrated to be green and efficient chiral organocatalysts for direct asymmetric aldol reactions at room temperature. The corresponding aldol products were obtained with moderate to good enantioselectivities. The influence of the presence of chirality in both the imidazolium cation and the prolinate anion on the transfer of chirality from the organocatalyst to the aldol product has been studied. Moreover, interesting match/mismatch situations have been observed regarding configuration of chirality of the two components through the analysis of results for organocatalysts derived from both enantiomers of prolinate (R/S) and the trans/cis isomers for the chiral fragment of the cation. This is associated with differences in the corresponding reaction rates but also to the different tendencies for the formation of aggregates, as evidenced by nonlinear effects studies (NLE). Excellent activities, selectivities, and enantioselectivities could be achieved by an appropriate selection of the structural elements at the cation and anion.
Project description:Methylation of lysine residues in histone proteins is catalyzed by S-adenosylmethionine (SAM)-dependent histone lysine methyltransferases (KMTs), a genuinely important class of epigenetic enzymes of biomedical interest. Here we report synthetic, mass spectrometric, NMR spectroscopic and quantum mechanical/molecular mechanical (QM/MM) molecular dynamics studies on KMT-catalyzed methylation of histone peptides that contain lysine and its sterically demanding analogs. Our synergistic experimental and computational work demonstrates that human KMTs have a capacity to catalyze methylation of slightly bulkier lysine analogs, but lack the activity for analogs that possess larger aromatic side chains. Overall, this study provides an important chemical insight into molecular requirements that contribute to efficient KMT catalysis and expands the substrate scope of KMT-catalyzed methylation reactions.
Project description:The linking of phosphoric acids via covalent or mechanical bonds has proven to be a successful strategy for the design of novel organocatalysts. Here, we present the first systematic investigation of singly-linked and macrocyclic bisphosphoric acids, including their synthesis and their application in phase-transfer and Brønsted acid catalysis. We found that the novel bisphosphoric acids show dramatically increased enantioselectivities in comparison to their monophosphoric acid analogues. However, the nature, length and number of linkers has a profound influence on the enantioselectivities. In the asymmetric dearomative fluorination via phase-transfer catalysis, bisphosphoric acids with a single, rigid bisalkyne-linker give the best results with moderate to good enantiomeric excesses. In contrast, bisphosphoric acids with flexible linkers give excellent enantioselectivities in the transfer-hydrogenation of quinolines via cooperative Brønsted acid catalysis. In the latter case, sufficiently long linkers are needed for high stereoselectivities, as found experimentally and supported by DFT calculations.
Project description:This report describes the development of an enantioselective C-N bond-forming reaction to produce 1,2,3,4-tetrahydroisoquinoline-derived cyclic aminals catalyzed by chiral phosphate anions. Central to the success of this goal was the design of a library of 3,3'-triazolyl BINOL-derived phosphoric acids capable of forming attractive hydrogen-bonding interactions with the peptide-like substrate. We envision this work will offer an alternative to the conventional strategy of increasing catalyst steric bulk to improve enantioselectivity with BINOL-derived phosphoric acids.
Project description:As cationic functional groups with excellent alkaline resistance that are potentially applicable to building blocks of robust anion exchange membrane (AEM) materials for water splitting and fuel cell modules, we describe the synthesis of triarylsulfonium (TAS) salts bearing sterically demanding substituents by the reaction of arynes with diaryl sulfides/sulfoxides and by the Friedel-Crafts reaction of diaryl sulfoxides. The TAS cations possessing three substituted benzene rings, such as tris(2,5-dimethylphenyl)sulfonium and bis(2,5-dimethylphenyl)mesitylsulfonium, were effectively produced through the appropriate choice of reactions and reagents. The alkaline stability of the TAS cations thus obtained was evaluated from their time-course 1H NMR spectra in 1 M KOH/CD3OD, from which the alkaline resistance of the TAS cations increased dramatically as the steric bulkiness of the aromatic substituents attached to the TAS cations increased. Among them, bis(2,5-dimethylphenyl)mesitylsulfonium was found to exhibit 25 times higher alkaline resistance performance compared to benzyltrimethylammonium, a conventional quaternary ammonium cation. The decomposition mechanism of the TAS cations in the basic methanol media was studied in detail, and it was concluded that the decomposition occurred by the nucleophilic ipso-substitution by the methoxide anions.