DFT-Based Stereochemical Rationales for the Bifunctional Brønsted Acid/Base-Catalyzed Diastereodivergent and Enantioselective aza-Henry Reactions of α-Nitro Esters.

A pair of chiral bis(amidine) [BAM] proton complexes provide reagent (catalyst)-controlled, highly diastereo- and enantioselective direct aza-Henry reactions leading to α-alkyl-substituted α,ß-diamino esters. A C2-symmetric ligand provides high anti-selectivity, while a nonsymmetric congener exhibits syn-selectivity in this example of diastereodivergent, enantioselective catalysis. A detailed computational analysis is reported for the first time, one that supports distinct models for selectivity resulting from the more hindered binding cavity of the C1-symmetric ligand. Binding in this congested pocket accommodates four hydrogen bond contacts among ligands and substrates, ultimately favoring a pre-syn arrangement highlighted by pyridinium-azomethine activation and quinolinium-nitronate activation. The complementary transition states reveal a wide range of alternatives. Comparing the C1- and C2-symmetric catalysts highlights distinct electrophile binding orientations despite their common hydrogen bond donor-acceptor features. Among the factors driving unusual high syn-diastereoselection are favorable dispersion forces that leverage the anthracenyl substituent of the C1-symmetric ligand.

Oxidative Rearrangement of MIDA (N-Methyliminodiacetic Acid) Boronates: Mechanistic Insights and Synthetic Applications.

Herein we report that coordinative hemilability allows the MIDA (N-methyliminodiacetic acid) nitrogen to behave as a nucleophile and intramolecularly intercept palladium π-allyl intermediates. A mechanistic investigation indicates that this rearrangement proceeds through an SN2-like displacement at tetrasubstituted boron to furnish novel DABN boronates. Oxidative addition into the N-C bond of the DABN scaffold furnishes borylated π-allyl intermediates that can then be trapped with a variety of nucleophiles, including in a three-component coupling.

Diversity-oriented synthesis of glycomimetics.

Glycomimetics are structural mimics of naturally occurring carbohydrates and represent important therapeutic leads in several disease treatments. However, the structural and stereochemical complexity inherent to glycomimetics often challenges medicinal chemistry efforts and is incompatible with diversity-oriented synthesis approaches. Here, we describe a one-pot proline-catalyzed aldehyde α-functionalization/aldol reaction that produces an array of stereochemically well-defined glycomimetic building blocks containing fluoro, chloro, bromo, trifluoromethylthio and azodicarboxylate functional groups. Using density functional theory calculations, we demonstrate both steric and electrostatic interactions play key diastereodiscriminating roles in the dynamic kinetic resolution. The utility of this simple process for generating large and diverse libraries of glycomimetics is demonstrated in the rapid production of iminosugars, nucleoside analogues, carbasugars and carbohydrates from common intermediates.

Discovery and Mechanistic Study of a Totally Organic C(aryl)-C(alkyl)Oxygen Insertion Reaction.

We report an unprecedented photochemical oxygen insertion reaction into an aromatic quinone methide. Insertion happens specifically within a C(aryl)-C(alkyl) bond, whereas the quinone methide moiety remains intact itself. Detailed mechanistic studies, supported by DFT calculations, support a pathway in which the p-QM plays a pivotal activating role.

Ligand Effect in Alkali-Metal-Catalyzed Transfer Hydrogenation of Ketones.

This work unveils the reactivity patterns, as well as ligand and additive effect on alkali-metal-base-catalyzed transfer hydrogenation of ketones. Crucially to this reactivity is the presence of a Lewis acid (alkali cation), as opposed to a simple base effect. With aryl ketones, the observed reactivity order is Na+ >Li+ >K+ , whereas for aliphatic substrates it follows the expected Lewis acidity, Li+ >Na+ >K+ . Importantly, the reactivity pattern can be drastically changed by adding ligands and additives. Kinetic, labelling, and competition experiments as well as DFT calculations suggested that the reaction proceeds through a concerted direct hydride-transfer mechanism, originally suggested by Woodward. The lithium cation was found to be intrinsically more active than heavier congeners, but in the case of aryl ketones a decrease in reaction rate was observed at ≈40 % conversion with lithium cations. Noncovalent-interaction analysis revealed that this deceleration effect originated from specific noncovalent interactions between the aryl moiety of 1-phenylethanol and the carbonyl group of acetophenone, which stabilize the product in the coordination sphere of lithium and thus poison the catalyst. The ligand/additive effect is a complicated phenomenon that includes a combination of several factors, such as the decrease of activation energy by ligation (confirmed by distortion/interaction calculations of N,N,N',N'-tetramethylethylenediamine, TMEDA) and the change in relative stabilization of reagents and substrates in the solution and the coordination sphere of the metal. Finally, we observed that lithium-base-catalyzed transfer hydrogenation can be further facilitated by the addition of an inexpensive and benign reagent, LiCl, which likely operates by re-initiating the reaction on a new lithium center.

Direct Observation and Analysis of the Halo-Amino-Nitro Alkane Functional Group.

Conventional amide synthesis is a mainstay in discipline-spanning applications, and it is a reaction type that historically developed as a singular paradigm when considering the carbon-nitrogen bond-forming step. Umpolung amide synthesis (UmAS) exploits the unique properties of an α-halo nitroalkane in its reaction with an amine to produce an amide. The "umpolung" moniker reflects its paradigm-breaking C-N bond formation on the basis of evidence that the nucleophilic nitronate carbon and electrophilic nitrogen engage to form a tetrahedral intermediate (TI) that is an unprecedented functional group, a 1,1,1-halo-amino-nitro alkane (HANA). Studies probing HANA transience have failed to capture this (presumably) highly reactive intermediate. We report here the direct observation of a HANA, its conversion thermally to an amide functionality, and quantitative analysis of this process using computational techniques. These findings validate the HANA as a functional group common to UmAS and diverted UmAS, opening the door to its targeted use and creative manipulation.

Synthesis of α-Borylated Ketones by Regioselective Wacker Oxidation of Alkenylboronates.

As part of a program aimed at metal-catalyzed oxidative transformations of molecules with carbon-metalloid bonds, the synthesis of α-borylated ketones is reported via regioselective TBHP-mediated Wacker-type oxidation of N-methyliminodiacetic acid (MIDA)-protected alkenylboronates. The observed regioselectivity correlates with the hemilabile nature of the B-N dative bond in the MIDA boronate functional group, which allows boron to guide selectivity through a neighboring group effect.