Utopia Point Bayesian Optimization Finds Condition-Dependent Selectivity for N-Methyl Pyrazole Condensation.

Utopia Point Bayesian Optimization (UPBO) was used to identify reaction conditions that are highly selective for the formation of N1 and N2-methyl-3-aryl pyrazole constitutional isomers. UPBO was used to explore a wide chemical space and identify basic reaction conditions for a typically acid-catalyzed Knorr pyrazole condensation. These studies revealed that selectivity in the reaction stems from a condition-dependent equilibrium of intermediates prior to dehydration. For the N2-methyl isomer reaction pathway, a hemiaminal intermediate was found to form reversibly under the reaction conditions, enabling a highly selective synthesis of the N2 isomer upon dehydrative workup. UPBO was able to successfully optimize conversion and selectivity simultaneously with search spaces of >1 million potential variable combinations without the need for high-performance computational resources.

Data-Driven Multi-Objective Optimization Tactics for Catalytic Asymmetric Reactions Using Bisphosphine Ligands.

Optimization of the catalyst structure to simultaneously improve multiple reaction objectives (e.g., yield, enantioselectivity, and regioselectivity) remains a formidable challenge. Herein, we describe a machine learning workflow for the multi-objective optimization of catalytic reactions that employ chiral bisphosphine ligands. This was demonstrated through the optimization of two sequential reactions required in the asymmetric synthesis of an active pharmaceutical ingredient. To accomplish this, a density functional theory-derived database of >550 bisphosphine ligands was constructed, and a designer chemical space mapping technique was established. The protocol used classification methods to identify active catalysts, followed by linear regression to model reaction selectivity. This led to the prediction and validation of significantly improved ligands for all reaction outputs, suggesting a general strategy that can be readily implemented for reaction optimizations where performance is controlled by bisphosphine ligands.

Atroposelective Negishi Coupling Optimization Guided by Multivariate Linear Regression Analysis: Asymmetric Synthesis of KRAS G12C Covalent Inhibitor GDC-6036.

An efficient asymmetric synthesis of a potent KRAS G12C covalent inhibitor, GDC-6036 (1), is reported. The synthesis features a highly atroposelective Negishi coupling to construct the key C-C bond between two highly functionalized pyridine and quinazoline moieties by employing a Pd/Walphos catalytic system. Statistical modeling by comparing computational descriptors of a range of Walphos chiral bisphosphine ligands to a training set of experimental results was used to inform the selection of the best ligand, W057-2, which afforded the desired Negishi coupling product (Ra)-3 in excellent selectivity. A subsequent telescoped reaction sequence of alkoxylation, global deprotection, and acrylamide formation, followed by a final adipate salt formation, furnished GDC-6036 (1) in 40% overall yield from starting materials pyridine 5 and quinazoline 6.

Asymmetric Hydrogenation of Unfunctionalized Tetrasubstituted Acyclic Olefins.

Asymmetric hydrogenation has evolved as one of the most powerful tools to construct stereocenters. However, the asymmetric hydrogenation of unfunctionalized tetrasubstituted acyclic olefins remains the pinnacle of asymmetric synthesis and an unsolved challenge. We report herein the discovery of an iridium catalyst for the first, generally applicable, highly enantio- and diastereoselective hydrogenation of such olefins and the mechanistic insights of the reaction. The power of this chemistry is demonstrated by the successful hydrogenation of a wide variety of electronically and sterically diverse olefins in excellent yield and high enantio- and diastereoselectivity.

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 E/Z 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 Z-selective in neat tetrahydrofuran (THF) and E-selective in 2.0 M THF/hexane. The results of NMR spectroscopy show the resulting enolates to be statistically distributed ensembles of E,E-, E,Z-, and Z,Z-enolate dimers with subunits that reflect the selectivities. The results of rate studies trace the preference for E and Z isomers to tetrasolvated- and pentasolvated-monomer-based transition structures, respectively. Enolization using LiHMDS in N,N-dimethylethylamine or triethylamine in toluene affords a 65:1 mixture of LiHMDS-lithium enolate mixed dimers containing E and Z 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.

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 E- or Z-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.

Mixed Aggregates of the Dilithiated Koga Tetraamine: NMR Spectroscopic and Computational Studies.

A combination of (1) H, (6) Li, (13) C, and (15) N NMR spectroscopies and density functional theory computations explores the formation of mixed aggregates by a dilithium salt of a C2 -symmetric chiral tetraamine (Koga's base). Lithium halides, acetylides, alkoxides, and monoalkylamides form isostructural trilithiated mixed aggregates with few exceptions. (6) Li-(13) C and (6) Li-(15) N couplings reveal heretofore undetected transannular contacts (laddering) with lithium acetylides and lithium monoalkylamides. Marked temperature-dependent (15) N chemical shifts seem to be associated with this laddering. Computational studies shed light on the general structures of the aggregates, their penchant for laddering, and the stereochemical consequences of aggregation.

Phosphoramidates as Steering Elements for Highly Selective Access to Complementary Imidazo[1,2-a]pyrimidine Isomers.

We report that selective N-phosphorylation of aminoimidazoles results in a key steering element that controls isomeric selectivity in the condensation of ß-ethoxy acrylamides and aminoimidazoles to furnish imidazo[1,2-a]pyrimidines. We identified conditions that provide highly selective (99:1) phosphorylation at the endo- or exocyclic nitrogen. Either the 2-amino or 4-amino isomer of the (benzo)imidazo[1,2-a]pyrimidine products could be isolated in 64-95% yield. Mass spectrometric analysis and computational studies give insight into the mechanism of this exceptionally selective transformation.