Case for Lithium Tetramethylpiperidide-Mediated Ortholithiations: Reactivity and Mechanisms

Rate and mechanistic studies of ortholithiations by lithium 2,2,6,6-tetramethylpiperidide focus on four arenes: 1,4-bis­(trifluoromethyl)­benzene, 1,3-bis­(trifluoromethyl)­benzene, 1,3-dimethoxybenzene, and 4,4-dimethyl-2-phenyl-2-oxazoline. Metalations occur via substrate-dependent combinations of monosolvated monomer, disolvated monomer, and tetrasolvated dimer (triple ions). Density functional theory computational studies augment the experimental data. We discuss the challenges presented by shifting dimer–monomer proportions in determining the observable reaction orders and our mathematical treatment of such shifting in reactant structure

Lithium Hexamethyldisilazide-Mediated Enolization of Highly Substituted Aryl Ketones: Structural and Mechanistic Basis of the <i>E</i>/<i>Z</i> Selectivities

Enolizations of highly substituted acyclic ketones used in the syntheses of tetrasubstituted olefin-based anticancer agents are described. Lithium hexamethyldisilazide (LiHMDS)-mediated enolizations are moderately <i>Z</i>-selective in neat tetrahydrofuran (THF) and <i>E</i>-selective in 2.0 M THF/hexane. The results of NMR spectroscopy show the resulting enolates to be statistically distributed ensembles of <i>E</i>,<i>E</i>-, <i>E</i>,<i>Z</i>-, and <i>Z</i>,<i>Z</i>-enolate dimers with subunits that reflect the selectivities. The results of rate studies trace the preference for <i>E</i> and <i>Z</i> isomers to tetrasolvated- and pentasolvated-monomer-based transition structures, respectively. Enolization using LiHMDS in <i>N</i>,<i>N</i>-dimethylethylamine or triethylamine in toluene affords a 65:1 mixture of LiHMDS–lithium enolate mixed dimers containing <i>E</i> and <i>Z</i> isomers, respectively. Spectroscopic studies show that condition-dependent complexation of ketone to LiHMDS occurs in trialkylamine/toluene. Rate data attribute the high selectivity exclusively to monosolvated-dimer-based transition structures

Data Science Guided Multiobjective Optimization of a Stereoconvergent Nickel-Catalyzed Reduction of Enol Tosylates to Access Trisubstituted Alkenes

Herein we report a method for a stereoconvergent synthesis of trisubstituted alkenes in two steps from simple ketone starting materials. The key step is a nickel-catalyzed reduction of the corresponding enol tosylates that predominantly relies on a monophosphine ligand to direct the stereoconvergent formation of either the E- or Z-trisubstituted alkene products. Reaction optimization was accomplished using a data science workflow including monophosphine training set design, statistical modeling, and multiobjective Bayesian optimization. The optimization campaign significantly improved access to both the E- and Z-trisubstituted products in up to ∼90:10 diastereoselectivity and >90% yield. After identifying superior ligands using training set design, only 25 reactions were required for each objective (E- and Z-isomer formation) to converge on improved reaction parameters from a search space of ∼30,000 potential conditions using the EDBO+ platform. Additionally, a hierarchical machine learning model was developed to predict the stereoselectivity of untested monophosphine ligands to achieve a validation mean absolute error (MAE) of 7.1% selectivity (0.21 kcal/mol). Ultimately, we present a synergistic data science workflow leveraging the integration of training set design, statistical modeling, and Bayesian optimization, thereby expanding access to stereodefined trisubstituted alkenes

Highly Stereoselective Synthesis of Tetrasubstituted Acyclic All-Carbon Olefins via Enol Tosylation and Suzuki–Miyaura Coupling

A highly stereocontrolled synthesis of tetrasubstituted acyclic all-carbon olefins has been developed via a stereoselective enolization and tosylate formation, followed by a palladium-catalyzed Suzuki–Miyaura cross-coupling of the tosylates and pinacol boronic esters in the presence of a Pd­(OAc)₂/RuPhos catalytic system. Both the enol tosylation and Suzuki–Miyaura coupling reactions tolerate an array of electronically and sterically diverse substituents and generate high yield and stereoselectivity of the olefin products. Judicious choice of substrate and coupling partner provides access to either the <i>E</i>- or <i>Z</i>-olefin with excellent yield and stereochemical fidelity. Olefin isomerization was observed during the Suzuki–Miyaura coupling. However, under the optimized cross-coupling reaction conditions, the isomerization was suppressed to <5% in most cases. Mechanistic probes indicate that the olefin isomerization occurs via an intermediate, possibly a zwitterionic palladium carbenoid species

Lithium Enolates in the Enantioselective Construction of Tetrasubstituted Carbon Centers with Chiral Lithium Amides as Noncovalent Stereodirecting Auxiliaries

Lithium enolates derived from carboxylic acids are ubiquitous intermediates in organic synthesis. Asymmetric transformations with these intermediates, a central goal of organic synthesis, are typically carried out with covalently attached chiral auxiliaries. An alternative approach is to utilize chiral reagents that form discrete, well-defined aggregates with lithium enolates, providing a chiral environment conducive of asymmetric bond formation. These reagents effectively act as noncovalent, or traceless, chiral auxiliaries. Lithium amides are an obvious choice for such reagents as they are known to form mixed aggregates with lithium enolates. We demonstrate here that mixed aggregates can effect highly enantioselective transformations of lithium enolates in several classes of reactions, most notably in transformations forming tetrasubstituted and quaternary carbon centers. Easy recovery of the chiral reagent by aqueous extraction is another practical advantage of this one-step protocol. Crystallographic, spectroscopic, and computational studies of the central reactive aggregate, which provide insight into the origins of selectivity, are also reported