Enantioselective Sulfonimidamide Acylation via a Cinchona Alkaloid-Catalyzed Desymmetrization: Scope, Data Science, and Mechanistic Investigation.

Methods to access chiral sulfur(VI) pharmacophores are of interest in medicinal and synthetic chemistry. We report the desymmetrization of unprotected sulfonimidamides via asymmetric acylation with a cinchona-phosphinate catalyst. The desired products are formed in excellent yield and enantioselectivity with no observed bis-acylation. A data-science-driven approach to substrate scope evaluation was coupled to high throughput experimentation (HTE) to facilitate statistical modeling in order to inform mechanistic studies. Reaction kinetics, catalyst structural studies, and density functional theory (DFT) transition state analysis elucidated the turnover-limiting step to be the collapse of the tetrahedral intermediate and provided key insights into the catalyst-substrate structure-activity relationships responsible for the origin of the enantioselectivity. This study offers a reliable method for accessing enantioenriched sulfonimidamides to propel their application as pharmacophores and serves as an example of the mechanistic insight that can be gleaned from integrating data science and traditional physical organic techniques.

Catalytic asymmetric C-H insertion reactions of vinyl carbocations.

From the preparation of pharmaceuticals to enzymatic construction of natural products, carbocations are central to molecular synthesis. Although these reactive intermediates are engaged in stereoselective processes in nature, exerting enantiocontrol over carbocations with synthetic catalysts remains challenging. Many resonance-stabilized tricoordinated carbocations, such as iminium and oxocarbenium ions, have been applied in catalytic enantioselective reactions. However, their dicoordinated counterparts (aryl and vinyl carbocations) have not, despite their emerging utility in chemical synthesis. We report the discovery of a highly enantioselective vinyl carbocation carbon-hydrogen (C-H) insertion reaction enabled by imidodiphosphorimidate organocatalysts. Active site confinement featured in this catalyst class not only enables effective enantiocontrol but also expands the scope of vinyl cation C-H insertion chemistry, which broadens the utility of this transition metal-free C(sp3)-H functionalization platform.

Noncovalent Stabilization of Radical Intermediates in the Enantioselective Hydroamination of Alkenes with Sulfonamides.

Noncovalent interactions (NCIs) are critical elements of molecular recognition in a wide variety of chemical contexts. While NCIs have been studied extensively for closed-shell molecules and ions, very little is understood about the structures and properties of NCIs involving free radical intermediates. In this report, we describe a detailed mechanistic study of the enantioselective radical hydroamination of alkenes with sulfonamides and present evidence suggesting that the basis for asymmetric induction in this process arises from attractive NCIs between a neutral sulfonamidyl radical intermediate and a chiral phosphoric acid (CPA). We describe experimental, computational, and data science-based evidence that identifies the specific radical NCIs that form the basis for the enantioselectivity. Kinetic studies support that C-N bond formation determines the enantioselectivity. Density functional theory investigations revealed the importance of both strong H-bonding between the CPA and the N-centered radical and a network of aryl-based NCIs that serve to stabilize the favored diastereomeric transition state. The contributions of these specific aryl-based NCIs to the selectivity were further confirmed through multivariate linear regression analysis by comparing the measured enantioselectivity to computed descriptors. These results highlight the power of NCIs to enable high levels of enantioselectivity in reactions involving uncharged open-shell intermediates and expand our understanding of radical-molecule interactions.

Exploring Structure-Function Relationships of Aryl Pyrrolidine-Based Hydrogen-Bond Donors in Asymmetric Catalysis Using Data-Driven Techniques.

Hydrogen bond-based organocatalysts rely on networks of attractive noncovalent interactions (NCIs) to impart enantioselectivity. As a specific example, aryl pyrrolidine substituted urea, thiourea, and squaramide organocatalysts function cooperatively through hydrogen bonding and difficult-to-predict NCIs as a function of the reaction partners. To uncover the synergistic effect of the structural components of this catalyst class, we applied data science tools to study various model reactions using a derivatized, aryl pyrrolidine-based, hydrogen-bond donor (HBD) catalyst library. Through a combination of experimentally collected data and data mined from previous reports, statistical models were constructed, illuminating the general features necessary for high enantioselectivity. A distinct dependence on the identity of the electrophilic reaction partner and HBD catalyst is observed, suggesting that a general interaction is conserved throughout the reactions analyzed. The resulting models also demonstrate predictive capability by the successful improvement of a previously reported reaction using out-of-sample reaction components. Overall, this study highlights the power of data science in exploring mechanistic hypotheses in asymmetric HBD catalysis and provides a prediction platform applicable in future reaction optimization.

Linear Regression Model Development for Analysis of Asymmetric Copper-Bisoxazoline Catalysis.

Multivariate linear regression analysis (MLR) is used to unify and correlate different categories of asymmetric Cu-bisoxazoline (BOX) catalysis. The versatility of Cu-BOX complexes has been leveraged for several types of enantioselective transformations including cyclopropanation, Diels-Alder cycloadditions and difunctionalization of alkenes. Statistical tools and extensive molecular featurization has guided the development of an inclusive linear regression model, providing a predictive platform and readily interpretable descriptors. Mechanism-specific categorization of curated datasets and parameterization of reaction components allows for simultaneous analysis of disparate organometallic intermediates such as carbenes and Lewis acid adducts, all unified by a common ligand scaffold and metal ion. Additionally, this workflow permitted the development of a complementary linear regression model correlating analogous BOX-catalyzed reactions employing Ni, Fe, Mg, and Pd complexes. Comparison of ligand parameters in each model reveals the relevant structural requirements necessary for high selectivity. Overall, this strategy highlights the utility of MLR analysis in exploring mechanistically driven correlations across a diverse chemical space in organometallic chemistry and presents an applicable workflow for related ligand classes.

Cobalt Catalyzed Reductive Spirocyclopropanation Reactions.

Cobalt pyridine-diimine (PDI) complexes catalyze the reductive spirocyclopropanation of terminal 1,3-dienes. gem-Dichlorocycloalkanes serve as carbene precursors and Zn is used as a terminal electron source. The reaction is effective for a range of gem-dichloro partners including those containing sulfur and nitrogen heterocycles. An example of an intramolecular Rh-catalyzed [5 + 2]-cycloaddition of a vinyl spirocyclopropane is demonstrated, providing rapid access to a complex tricyclic framework. Overall, this catalyst system is capable of suppressing the kinetically facile 1,2-hydride shift, which has hampered the development of Simmons-Smith reactions using Zn carbenoids possessing ß-hydrogen atoms.

Connecting and Analyzing Enantioselective Bifunctional Hydrogen Bond Donor Catalysis Using Data Science Tools.

The generalization of related asymmetric processes in organocatalyzed reactions is an ongoing challenge due to subtle, noncovalent interactions that drive selectivity. The lack of transferability is often met with a largely empirical approach to optimizing catalyst structure and reaction conditions. This has led to the development of diverse structural catalyst motifs and inspired unique design principles in this field. Bifunctional hydrogen bond donor (HBD) catalysis exemplifies this in which a broad collection of enantioselective transformations has been successfully developed. Herein, we describe the use of data science methods to connect catalyst and substrate structural features of an array of reported enantioselective bifunctional HBD catalysis through an iterative statistical modeling process. The computational parameters used to build the correlations are mechanism-specific based on the proposed transition states, which allows for analysis into the noncovalent interactions responsible for asymmetric induction. The resulting statistical models also allow for extrapolation to out-of-sample examples to provide a prediction platform that can be used for future applications of bifunctional hydrogen bond donor catalysis. Finally, this multireaction workflow presents an opportunity to build statistical models unifying various modes of activation relevant to asymmetric organocatalysis.

Cobalt-Catalyzed Reductive Dimethylcyclopropanation of 1,3-Dienes.

Dimethylcyclopropanes are valuable synthetic targets that are challenging to access in high yield using Zn carbenoid reagents. Herein, we describe a cobalt-catalyzed variant of the Simmons-Smith reaction that enables the efficient dimethylcyclopropanation of 1,3-dienes using a Me2 CCl2 /Zn reagent mixture. The reactions proceed with high regioselectivity based on the substitution pattern of the 1,3-diene. The products are vinylcyclopropanes, which serve as substrates for transition-metal-catalyzed ring-opening reactions, including 1,3-rearrangement and [5+2] cycloaddition. Preliminary studies indicate that moderately activated monoalkenes are also amenable to dimethylcyclopropanation under the conditions of cobalt catalysis.

Regioselective Simmons-Smith-type cyclopropanations of polyalkenes enabled by transition metal catalysis.

A [ i-PrPDI]CoBr2 complex (PDI = pyridine-diimine) catalyzes Simmons-Smith-type reductive cyclopropanation reactions using CH2Br2 in combination with Zn. In contrast to its non-catalytic variant, the cobalt-catalyzed cyclopropanation is capable of discriminating between alkenes of similar electronic properties based on their substitution patterns: monosubstituted > 1,1-disubstituted > (Z)-1,2-disubstituted > (E)-1,2-disubstituted > trisubstituted. This property enables synthetically useful yields to be achieved for the monocyclopropanation of polyalkene substrates, including terpene derivatives and conjugated 1,3-dienes. Mechanistic studies implicate a carbenoid species containing both Co and Zn as the catalytically relevant methylene transfer agent.

Dehydrogenative Transformations of Imines Using a Heterogeneous Photocatalyst.

Heterogeneous semiconductors are underexploited as photoredox catalysts in organic synthesis relative to their homogeneous, molecular counterparts. Here, we report the use of metal/TiO2 particles as catalysts for light-induced dehydrogenative imine transformations. The highly oxophilic nature of the TiO2 surface promotes the selective binding and dehydrogenation of alcohols in the presence of other oxidizable and Lewis basic functional groups. This feature enables the clean photogeneration of aldehyde equivalents that can be utilized in multicomponent couplings.