Enantio- and Diastereoselective Variations on α-Iminonitriles: Harnessing Chiral Cyclopropenimine-Thiourea Organocatalysts.

Chiral 1-pyrrolines containing a nitrile motif serve as crucial structural scaffolds in biologically active molecules and exhibit diversity as building blocks owing to their valuable functional groups; however, the asymmetric synthesis of such compounds remains largely unexplored. Herein, we present an enantio- and diastereoselective method for the synthesis of α-chiral nitrile-containing 1-pyrroline derivatives bearing vicinal stereocenters through the design and introduction of chiral cyclopropenimine-based bifunctional catalysts featuring a thiourea moiety. This synthesis entails a highly stereoselective conjugate addition of α-iminonitriles to a wide array of enones, followed by cyclocondensation, thereby affording a series of cyanopyrroline derivatives, some of which contain all-carbon quaternary centers. Moreover, we demonstrate the synthetic utility of this strategy by performing a gram-scale reaction with 1% catalyst loading, along with a variety of chemoselective transformations of the product, including the synthesis of a vildagliptin analogue. Finally, we showcase the selective synthesis of all four stereoisomers of the cyanopyrroline products through trans-to-cis isomerization, highlighting the versatility of our approach.

Copper-Catalyzed C-C Cross-Couplings of Tertiary Alkyl Halides with Anilines Enabled by Cyclopropenimine-Based Ligands.

Catalytic cross-couplings of tertiary alkyl electrophiles with carbon nucleophiles offer a powerful platform for constructing quaternary carbon centers, which are prevalent in bioactive molecules. However, these reactions remain underdeveloped primarily because of steric challenges that impede efficient bond formation. Herein, we describe the copper-catalyzed synthesis of such centers through the C(sp3)-C(sp2) bond-forming reaction between tertiary alkyl halides and arene rings of aniline derivatives, enabled by the strategic implementation of bidentate bis(cyclopropenimine) ligands. The copper catalyst bound by two imino-nitrogen atoms of these ligands, which have never been employed in metal catalysis previously, is highly effective in rapidly activating tertiary halides to generate alkyl radicals, allowing them to react with aryl nucleophiles under mild conditions with remarkably short reaction times (1-2 h). Various tertiary halides bearing carbonyl functional groups can be coupled with secondary or primary anilines, furnishing a range of quaternary carbon centers in good yields. Several mechanistic observations support the generation of copper(II) species and alkyl radicals which as a result elucidate the steps in the proposed catalytic cycle.

Direct Arylation of Simple Arenes with Aryl Bromides by Synergistic Silver and Palladium Catalysis.

The direct, catalytic arylation of simple arenes in small excess with aryl bromides is disclosed. The developed method does not require the assistance of directing groups and relies on a synergistic catalytic cycle in which phosphine-ligated silver complexes cleave the aryl C-H bond, while palladium catalysts enable the formation of the biaryl products. Mechanistic experiments, including kinetic isotope effects, competition experiments, and hydrogen-deuterium exchange, support a catalytic cycle in which cleavage of the C-H bond by silver is the rate-determining step.

Stereodivergent silver-catalyzed synthesis of pyroglutamic acid esters.

We report here a silver-catalyzed method for the enantio- and diastereodivergent synthesis of chiral pyroglutamic acid esters with multiple stereocenters. This process proceeds through asymmetric conjugate addition of glycine imine esters to a broad range of ß-substituted α,ß-unsaturated perfluorophenyl esters followed by lactamization. By leveraging catalyst control and stereospecificity of the 1,4-addition process, all four product stereoisomers containing two adjacent stereocenters are accessible with high stereoselectivity.

Computational Screening of Trillions of Metal-Organic Frameworks for High-Performance Methane Storage.

In the past decade, there has been an increasing number of computational screening works to facilitate finding optimal materials for a variety of different applications. Unfortunately, most of these screening studies are limited to their initial set of materials and result in a brute-force type of screening approach. In this work, we present a systematic strategy that can find metal-organic frameworks (MOFs) with the desired properties from an extremely diverse and large set of over 100 trillion possible MOFs using machine learning and evolutionary algorithm. It is demonstrated that our algorithm can discover 964 MOFs with methane working capacity over 200 cm3 cm-3 and 96 MOFs with methane working capacity over the current world record of 208 cm3 cm-3. We believe that this methodology can take advantage of the modular nature of MOFs and can readily be extended to other important applications as well.

Stereodivergent Carbon-Carbon Bond Formation between Iminium and Enolate Intermediates by Synergistic Organocatalysis.

We report here a stereodivergent method for the Michael addition of aryl acetic acid esters to α,ß-unsaturated aldehydes catalyzed by a combination of a chiral pyrrolidine and a chiral Lewis base. This reaction proceeds through a synergistic catalytic cycle which consists of one cycle leading to a chiral iminium electrophile and a second cycle generating a nucleophilic chiral enolate for the construction of a carbon-carbon bond. By varying the combinations of catalyst enantiomers, all four stereoisomers of the products with two vicinal stereocenters are accessible with high enantio- and diastereoselectivity. The products of the Michael addition, 1,5-aldehyde esters, can be readily transformed into a variety of other valuable enantioenriched structures, including those bearing three contiguous stereocenters in an acyclic system, thus providing an efficient route to an array of structural and stereochemical diversity.

Boron Lewis Acid-Catalyzed Hydrophosphinylation of N-Heteroaryl-Substituted Alkenes with Secondary Phosphine Oxides.

We report the boron-catalyzed hydrophosphinylation of N-heteroaryl-substituted alkenes with secondary phosphine oxides that furnishes various phosphorus-containing N-heterocycles. This process proceeds under mild conditions and enables the introduction of a phosphorus atom into multisubstituted alkenylazaarenes. The available mechanistic data can be explained by a reaction pathway wherein the C-P bond is created by the reaction between the activated alkene (by coordination to a boron catalyst) and the phosphorus(III) nucleophile (in tautomeric equilibrium with phosphine oxide).

Lewis acid-catalyzed double addition of indoles to ketones: synthesis of bis(indolyl)methanes with all-carbon quaternary centers.

We report herein a Lewis acid-catalyzed nucleophilic double-addition of indoles to ketones under mild conditions. This process occurs with various ketones ranging from dialkyl ketones to diaryl ketones, thereby providing access to an array of bis(indolyl)methanes bearing all-carbon quaternary centers, including tetra-aryl carbon centers. The products can be transformed into bis(indole)-fused polycyclics and bis(indolyl)alkenes.

Palladium-Catalyzed, Site-Selective Direct Allylation of Aryl C-H Bonds by Silver-Mediated C-H Activation: A Synthetic and Mechanistic Investigation.

We describe a method for the site-selective construction of a C(aryl)-C(sp3) bond by the palladium-catalyzed direct allylation of arenes with allylic pivalates in the presence of AgOPiv to afford the linear (E)-allylated arene with excellent regioselectivity; this reaction occurs with arenes that have not undergone site-selective and stereoselective direct allylation previously, such as monofluorobenzenes and non-fluorinated arenes. Mechanistic studies indicate that AgOPiv ligated by a phosphine reacts with the arene to form an arylsilver(I) species, presumably through a concerted metalation-deprotonation pathway. The activated aryl moiety is then transferred to an allylpalladium(II) intermediate formed by oxidative addition of the allylic pivalate to the Pd(0) complex. Subsequent reductive elimination furnishes the allyl-aryl coupled product. The aforementioned proposed intermediates, including an arylsilver complex, have been isolated, structurally characterized, and determined to be chemically and kinetically competent to undergo the proposed elementary steps of the catalytic cycle.

Phosphine-catalyzed enantioselective intramolecular [3+2] annulations to generate fused ring systems.

Substantial progress has been described in the development of asymmetric variants of the phosphine-catalyzed intermolecular [3+2] annulation of allenes with alkenes; however, there have not been corresponding advances for the intramolecular process, which can generate a higher level of complexity (an additional ring and stereocenter(s)). In this study, we describe the application of chiral phosphepine catalysts to address this challenge, thereby providing access to useful scaffolds that are found in bioactive compounds, including diquinane and quinolin-2-one derivatives, with very good stereoselectivity. The products of the [3+2] annulation can be readily transformed into structures that are even more stereochemically rich. Mechanistic studies are consistent with ß addition of the phosphepine to the allene being the turnover-limiting step of the catalytic cycle, followed by a concerted [3+2] cycloaddition to the pendant olefin.

Enantioselective nucleophile-catalyzed synthesis of tertiary alkyl fluorides via the α-fluorination of ketenes: synthetic and mechanistic studies.

The catalytic asymmetric synthesis of alkyl fluorides, particularly α-fluorocarbonyl compounds, has been the focus of substantial effort in recent years. While significant progress has been described in the formation of enantioenriched secondary alkyl fluorides, advances in the generation of tertiary alkyl fluorides have been more limited. Here, we describe a method for the catalytic asymmetric coupling of aryl alkyl ketenes with commercially available N-fluorodibenzenesulfonimide (NFSI) and C6F5ONa to furnish tertiary α-fluoroesters. Mechanistic studies are consistent with the hypothesis that the addition of an external nucleophile (C6F5ONa) is critical for turnover, releasing the catalyst (PPY*) from an N-acylated intermediate. The available data can be explained by a reaction pathway wherein the enantioselectivity is determined in the turnover-limiting transfer of fluorine from NFSI to a chiral enolate derived from the addition of PPY* to the ketene. The structure and the reactivity of the product of this proposed elementary step, an α-fluoro-N-acylpyridinium salt, have been examined.

Nonenzymatic dynamic kinetic resolution of secondary alcohols via enantioselective acylation: synthetic and mechanistic studies.

Because of the ubiquity of the secondary carbinol subunit, the development of new methods for its enantioselective synthesis remains an important ongoing challenge. In this report, we describe the first nonenzymatic method for the dynamic kinetic resolution (DKR) of secondary alcohols (specifically, aryl alkyl carbinols) through enantioselective acylation, and we substantially expand the scope of this approach, vis-à-vis enzymatic reactions. Simply combining an effective process for the kinetic resolution of alcohols with an active catalyst for the racemization of alcohols did not lead to DKR, due to the incompatibility of the ruthenium-based racemization catalyst with the acylating agent (Ac(2)O) used in the kinetic resolution. A mechanistic investigation revealed that the ruthenium catalyst is deactivated through the formation of a stable ruthenium-acetate complex; this deleterious pathway was circumvented through the appropriate choice of acylating agent (an acyl carbonate). Mechanistic studies of this new process point to reversible N-acylation of the nucleophilic catalyst, acyl transfer from the catalyst to the alcohol as the rate-determining step, and carbonate anion serving as the Brønsted base in that acyl-transfer step.