Project description:We report the application of peptide-embedded imidazoles as catalysts for the site-selective delivery of the phenyl thionoformate unit as a prelude to deoxygenation reactions of polyols. Methodology was developed that allows for the synthesis of thiocarbonyl derivatives based on a combination of additives that include N-alkylimidazoles and FeCl3 as co-catalysts. The use of this reagent combination leads to increased reaction rates and efficient yields relative to those of simple base-mediated reactions. In terms of controlling regioselectivity during the course of polyol modification, we found that histidine-containing peptides, in combination with FeCl3, could lead to modulation of the product distribution. Through screening of peptides and control of reaction conditions, products could be observed that reflected both the inherent preference of substrates and also reversal of inherent selectivity.
Project description:New phosphoramidite complexes of iron were synthesized and structurally characterized. Reaction of the known chiral phosphoramidites (RO)2PNR'2 (R = binaphthyl, R' = CH3, 1a; R = binaphthyl, R' = benzyl, 1b) with [FeBr(Cp)(CO)2] afforded the title compounds [FeBr(Cp)(CO)(1a,b)] (4a,b) in 34 and 65 % isolated yields as mixtures of diastereomers, since both the metal and the ligand are stereogenic. Similarly, reaction of 1b with [Fe(Cp)I(CO)2] in the presence of catalytic [Fe(Cp)(CO)2]2 afforded [Fe(Cp)I(CO)(1b)] (5b) in 81% yield as a mixture of diastereomers. The molecular structures of 4a, 4b and 5 were determined, revealing a pseudo octahedral coordination geometry about the iron center. The new metal complexes are catalytically active in the oxidation of benzylic methylene groups to the corresponding ketones, utilizing t-BuOOH as oxidant (2 mol% catalyst, 36 h, room temperature, 31-80% yield).
Project description:Despite the ubiquitous use of phosphoramidite chemistry in the synthesis of biophosphates, catalytic asymmetric phosphoramidite transfer remains largely unexplored for phosphate ester synthesis. We have discovered that a tetrazole-functionalized peptide, in the presence of 10-Å molecular sieves, functions as an enantioselective catalyst for phosphite transfer. This chemistry in turn has been used as the key step in a streamlined synthesis of myo-inositol-6-phosphate. Mechanistic insights implicate phosphate as a directing group for a highly selective kinetic resolution of a protected inositol monophosphate. This work represents a distinct and efficient method for the selective catalytic phosphorylation of natural products.
Project description:Monodentate phosphoramidite ligands have been developed based on enantiopure 6,6'-dimethylbiphenols with axial chirality. These chiral ligands are easy to prepare and flexible for modifications. The fine-tuning capability of these ligands plays a significant role in achieving high enantioselectivity in the asymmetric hydroformylation of allyl cyanide and the conjugate addition of diethylzinc to cycloalkenones.
Project description:Selective deuterium installation into small molecules is becoming increasingly desirable not only for the elucidation of mechanistic pathways and studying biological processes but also because of deuterium's ability to favorably adjust the pharmacokinetic parameters of bioactive molecules. Fused bicyclic moieties, especially those containing heteroatoms, are prevalent in drug discovery and pharmaceuticals. Herein, we report a copper-catalyzed transfer hydrodeuteration of cyclic and heterocyclic alkenes, which enables the synthesis of chromans, quinolinones, and tetrahydronaphthalenes that are precisely deuterated at the benzylic position. We also demonstrate the ability to place one deuterium atom at the homobenzylic site of these scaffolds with high regioselectivity by swapping transfer reagents for their isotopic analogs. Furthermore, examples of chemoselective transfer hydrogenation and transfer deuteration are disclosed, allowing for the simultaneous incorporation of two vicinal hydrogen or deuterium atoms into a double bond.
Project description:Direct peptide and protein activation is a challenging transformation because of the stabilizing effect of the amide group. While enzymes can be considered as prototypical systems that have evolved to achieve high selectivity and specificity, small-molecule catalysts that functionalize the amide group may accommodate a much larger selection of substrates but currently remain scarce. Here, by combining the desired features from both catalytic regimes we designed an artificial cyclodehydratase, a catalytic system for the site-selective modification of peptides and natural products by engrafting heterocycles into their scaffolds. The catalytic system features a molybdenum(VI) center that was decorated with a sterically congested tripod ligand. The optimized catalyst can introduce azolines into small molecules, natural products, and oligopeptides with high efficiency and minimal waste. We further demonstrate the utility of the new protocol in the direct functionalization of a single amide group in the presence of up to seven other chemically similar positions and in the direct conversion of these groups into amines and thioamides. This new mechanistic paradigm may address an unmet need for a general method for the selective and sustainable functionalization of peptides and natural products.
Project description:Many biomedical fields rely on proteins that are selectively modified. These can be attached using reactive or catalytic moieties, but the position where these moieties are attached is often poorly controlled. We assessed how catalyst position affects the efficiency and selectivity of protein modification. For this, we anchored a template DNA strand to three different proteins, which were subsequently hybridized to DNA strands that contained catalysts at different positions. We found a strong correlation between the catalyst-to-protein distance and the efficiency of protein modification for acyl transfer catalysts, which operate via a covalently bound reactant intermediate. Additionally, we found that the catalyst's distance and orientation with respect to the protein surface, also influences its site-selectivity. A catalyst operating with unbound reactant intermediates showed only enhanced efficiency. Our results are rationalized using computational simulations, showing that one-point anchoring of the DNA construct leads to notable differences in the site of modification.
Project description:Chemists have long sought the ability to modify molecules precisely when presented with several sites of similar reactivity. We reasoned that the confinement of substrates within nanostructures might permit site-selective reactions unachievable in bulk solution, even with sophisticated reagents. In particular, the stretching and alignment of polymers within nanotubes might allow site-specific cleavage or modification. To explore this proposition, macromolecular disulfide substrates were elongated within members of a collection of tubular protein nanoreactors, which contained cysteine residues positioned at different locations along the length of each tube. For each nanoreactor, we defined the reactive location by using a set of polymer substrates (site-selectivity) and which of the two sulfur atoms was attacked (regioselectivity), and found that disulfide interchange occurs with atomic precision. Our strategy has potential for the selective processing of a wide variety of biomacromolecules, and the chemistry and substrates might be generalized yet further by using alternative nanotubes.
Project description:Primary amines are common functional groups in the reaction environment surrounding an (electro)catalyst, and this includes catalysts ranging from metalloenzymes surrounded by amino acids, to electrocatalysts operating in amine industrial sorbents for CO2 capture and conversion. This report explores the behavior of amine functional groups at the surface of an electrocatalyst. The possible effects of those amine secondary coordination sphere (SCS) groups on a CO2 electro-reduction mechanism include stabilization of intermediates and positioning substrate near the active site. Two different clusters were synthesized: [PPN][Fe4N(CO)11(Ph2PCH2CH2NH2)] (PPN-1) has one amine, and [PPN][Fe4N(CO)10(Ph2PCH2CH2NH2)2] (PPN-2) has two covalently appended amine functional groups (PPN: bis(triphenylphosphine)iminium). Infra-red spectroscopic studies show a direct reaction of each cluster with CO2 to afford an SCS carbamate functional group, and cyclic voltammetry investigations reveal a variety of roles for the amine SCS groups in the mechanism of catalyst hydride formation and hydride transfer (HT) to CO2. The most prominent effect of the amine functional group is stabilization of the intermediate hydride to lower formate yield. With PPN-1, these combined effects serve to shut down HT to CO2. With PPN-2, the combined effects result in some loss of selectivity, so that formate and H2 mixtures (6 : 1) are obtained.
Project description:Nitrogen modified cobalt catalysts supported on carbon were prepared by pyrolysis of the mixture generated from cobalt(ii) acetate in aqueous solution of melamine or waste melamine resins, which are widely used as industrial polymers. The obtained nanostructured materials catalyze the transfer hydrogenation of N-heteroarenes with formic acid in the absence of base. The optimal Co/Melamine-2@C-700 catalyst exhibits high activity and selectivity for the dehydrogenation of formic acid into molecular hydrogen and carbon dioxide and allows for the reduction of diverse N-heteroarenes including substrates featuring sensitive functional groups.