A General Strategy for N-(Hetero)arylpiperidine Synthesis Using Zincke Imine Intermediates.

Methods to synthesize diverse collections of substituted piperidines are valuable due to the prevalence of this heterocycle in pharmaceutical compounds. Here, we present a general strategy to access -(hetero)arylpiperidines using a pyridine ring-opening and ring-closing approach via Zincke imine intermediates. This process generates pyridinium salts from a wide variety of substituted pyridines and (heteroaryl)anilines; hydrogenation reactions and nucleophilic additions then access the -(hetero)arylpiperidine derivatives.

A Unified Strategy to Fluorinated Nucleoside Analogues an Electrophilic Manifold.

Herein, we present a strategy for the preparation of 3'-fluorinated nucleoside analogues the aminocatalytic, electrophilic fluorination of readily accessible and bench-stable 2'-ketonucleosides. Initially developed to facilitate the manufacture of 3'-fluoroguanosine (3'-FG)─a substructure of anticancer therapeutic MK-1454─this strategy has been extended to the synthesis of a variety of 3'-fluoronucleosides. Finally, we demonstrate the utility of the 2'-ketonucleoside synthon as a platform for further diversification and suggest that this methodology should be broadly applicable to the discovery of novel nucleoside analogues.

Diverse Catalytic Reactions for the Stereoselective Synthesis of Cyclic Dinucleotide MK-1454.

As practitioners of organic chemistry strive to deliver efficient syntheses of the most complex natural products and drug candidates, further innovations in synthetic strategies are required to facilitate their efficient construction. These aspirational breakthroughs often go hand-in-hand with considerable reductions in cost and environmental impact. Enzyme-catalyzed reactions have become an impressive and necessary tool that offers benefits such as increased selectivity and waste limitation.

Low-Molecular-Weight Branched Polyethylenimine Potentiates Ampicillin against MRSA Biofilms.

Methicillin-resistant (MRSA) infections pose a serious threat worldwide. MRSA is the predominant species isolated from medical-device-related biofilm infections and chronic wounds. Its ability to form biofilms grants it resistance to almost all antibiotics on the market.

Discovery of a Photoinduced Dark Catalytic Cycle Using in Situ LED-NMR Spectroscopy.

We report the use of LED-NMR spectroscopy to study the reaction mechanism of a newly discovered photoinduced iron-catalyzed cycloisomerization of alkynols to cyclic enol ethers. By understanding on/off ligand binding to the catalyst, we were able to appropriately design reaction conditions to balance catalyst activity and stability. LED-NMR was demonstrated to be a powerful tool in elucidating reaction mechanisms of photochemical reactions.

Mild Synthesis of Substituted 1,2,5-Oxadiazoles Using 1,1'-Carbonyldiimidazole as a Dehydrating Agent.

1,1'-Carbonyldiimidazole was found to induce the formation of a variety of 3,4-disubstituted 1,2,5-oxadiazoles (furazans) from the corresponding bisoximes at ambient temperature. This method enables these inherently energetic compounds to be prepared at temperatures well below their decomposition points and with improved functional group compatibility relative to prior methods. Conditions were developed that allowed for the first high-yielding synthesis of chlorofurazans from their amino counterparts, enabling the mild synthetic manipulation of these heterocycles.

Exploiting non-covalent π interactions for catalyst design.

Molecular recognition, binding and catalysis are often mediated by non-covalent interactions involving aromatic functional groups. Although the relative complexity of these so-called π interactions has made them challenging to study, theory and modelling have now reached the stage at which we can explain their physical origins and obtain reliable insight into their effects on molecular binding and chemical transformations. This offers opportunities for the rational manipulation of these complex non-covalent interactions and their direct incorporation into the design of small-molecule catalysts and enzymes.

Enantiodivergent Fluorination of Allylic Alcohols: Data Set Design Reveals Structural Interplay between Achiral Directing Group and Chiral Anion.

Enantioselectivity values represent relative rate measurements that are sensitive to the structural features of the substrates and catalysts interacting to produce them. Therefore, well-designed enantioselectivity data sets are information rich and can provide key insights regarding specific molecular interactions. However, if the mechanism for enantioselection varies throughout a data set, these values cannot be easily compared.

Organic chemistry. A data-intensive approach to mechanistic elucidation applied to chiral anion catalysis.

Knowledge of chemical reaction mechanisms can facilitate catalyst optimization, but extracting that knowledge from a complex system is often challenging. Here, we present a data-intensive method for deriving and then predictively applying a mechanistic model of an enantioselective organic reaction. As a validating case study, we selected an intramolecular dehydrogenative C-N coupling reaction, catalyzed by chiral phosphoric acid derivatives, in which catalyst-substrate association involves weak, noncovalent interactions.

Asymmetric cross-dehydrogenative coupling enabled by the design and application of chiral triazole-containing phosphoric acids.

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.

Dynamic kinetic asymmetric synthesis of substituted pyrrolidines from racemic cyclopropanes and aldimines: reaction development and mechanistic insights.

An enantioselective preparation of 2,5-cis-disubstituted pyrrolidines has been achieved via a dynamic kinetic asymmetric transformation (DyKAT) of racemic donor-acceptor cyclopropanes and (E)-aldimines. Mechanistic studies suggest that isomerization of the aldimine or resultant iminium to the Z geometry is not a pathway that furnishes the observed 2,5-cis-disubstituted products.