Synthesis of Diverse β-Quaternary Ketones via Palladium-Catalyzed Asymmetric Conjugate Addition of Arylboronic Acids to Cyclic Enones

The development and optimization of a palladium-catalyzed asymmetric conjugate addition of arylboronic acids to cyclic enone conjugate acceptors is described. These reactions employ air-stable and readily-available reagents in an operationally simple and robust transformation that yields β-quaternary ketones in high yields and enantioselectivities. Notably, the reaction itself is highly tolerant of atmospheric oxygen and moisture and therefore does not require the use of dry or deoxygenated solvents, specially purified reagents, or an inert atmosphere. The ring size and β-substituent of the enone are highly variable, and a wide variety of β-quaternary ketones can be synthesized. More recently, the use of NH_4PF_6 has further expanded the substrate scope to include heteroatom-containing arylboronic acids and β-acyl enone substrates

An Efficient Protocol for the Palladium-Catalyzed Asymmetric Decarboxylative Allylic Alkylation Using Low Palladium Concentrations and a Palladium(II) Precatalyst

Enantioselective catalytic allylic alkylation for the synthesis of 2-alkyl-2-allylcycloalkanones and 3,3-disubstituted pyrrolidinones, piperidinones and piperazinones has been previously reported by our laboratory. The efficient construction of chiral all-carbon quaternary centers by allylic alkylation was previously achieved with a catalyst derived in situ from zero-valent palladium sources and chiral phosphinooxazoline (PHOX) ligands. We now report an improved reaction protocol with broad applicability among different substrate classes in industry-compatible reaction media using loadings of palladium(II) acetate as low as 0.075 mol% and the readily available chiral PHOX ligands. The novel and highly efficient procedure enables facile scale-up of the reaction in an economical and sustainable fashion

Palladium-Catalyzed Asymmetric Conjugate Addition of Arylboronic Acids to Heterocyclic Acceptors

Flava Flavanone: Asymmetric conjugate additions to chromones and 4-quinolones are reported utilizing a single catalyst system formed in situ from Pd(OCOCF_3)_2 and (S)-tBuPyOX. Notably, these reactions are performed in wet solvent under ambient atmosphere, and employ readily available arylboronic acids as the nucleophile, thus providing ready access to these asymmetric heterocycles

Expanding Insight into Asymmetric Palladium-Catalyzed Allylic Alkylation of N-Heterocyclic Molecules and Cyclic Ketones

Eeny, meeny, miny … enaminones! Lactams and imides have been shown to consistently provide enantioselectivities substantially higher than other substrate classes previously investigated in the palladium-catalyzed asymmetric decarboxylative allylic alkylation. Several new substrates have been designed to probe the contributions of electronic, steric, and stereoelectronic factors that distinguish the lactam/imide series as superior alkylation substrates (see scheme). These studies culminated in marked improvements on carbocyclic allylic alkylation substrates

Mechanism and Enantioselectivity in Palladium-Catalyzed Conjugate Addition of Arylboronic Acids to β‑Substituted Cyclic Enones: Insights from Computation and Experiment

Enantioselective conjugate additions of arylboronic acids to β-substituted cyclic enones have been previously reported from our laboratories. Air- and moisture-tolerant conditions were achieved with a catalyst derived in situ from palladium(II) trifluoroacetate and the chiral ligand (S)-t-BuPyOx. We now report a combined experimental and computational investigation on the mechanism, the nature of the active catalyst, the origins of the enantioselectivity, and the stereoelectronic effects of the ligand and the substrates of this transformation. Enantioselectivity is controlled primarily by steric repulsions between the t-Bu group of the chiral ligand and the α-methylene hydrogens of the enone substrate in the enantiodetermining carbopalladation step. Computations indicate that the reaction occurs via formation of a cationic arylpalladium(II) species, and subsequent carbopalladation of the enone olefin forms the key carbon–carbon bond. Studies of nonlinear effects and stoichiometric and catalytic reactions of isolated (PyOx)Pd(Ph)I complexes show that a monomeric arylpalladium–ligand complex is the active species in the selectivity-determining step. The addition of water and ammonium hexafluorophosphate synergistically increases the rate of the reaction, corroborating the hypothesis that a cationic palladium species is involved in the reaction pathway. These additives also allow the reaction to be performed at 40 °C and facilitate an expanded substrate scope

Development of a palladium-catalyzed enantioselective conjugate addition of arylboronic acids to cyclic conjugate acceptors

The first enantioselective Pd-catalyzed construction of all-carbon quaternary stereocenters via 1,4-addn. of arylboronic acids to β-substituted cyclic enones is reported. Reaction of a wide range of arylboronic acids and cyclic enones using a catalyst prepd. from Pd(OCOCF_3)_2 and a chiral pyridinooxazoline ligand yields enantioenriched products bearing benzylic stereocenters. Notably, this transformation is tolerant to air and moisture, providing a practical and operationally simple method of synthesizing enantioenriched all-carbon quaternary stereocenters

Development and application of a palladium-​catalyzed enantioselective conjugate addition

The first enantioselective palladium-catalyzed, asym. construction of all-carbon quaternary stereocenters via 1, 4-addn. of arylboronic acids to cyclic, β-substituted enones is reported. A wide range of arylboronic acids and cyclic enones are reacted utilizing a catalyst prepd. from palladium(II) trifluoroacetate and a chiral pyridinooxazoline ligand to yield enantioenriched products bearing benzylic stereocenters. Recently, this methodol. has been expanded to support the reaction of heterocyclic chromone and 4-quinolone conjugate acceptors. Notably, this transformation is insensitive to air or moisture, providing a practical and operationally simple method of synthesizing enantioenriched stereocenters. The application of this reaction toward the total syntheses of members of the taiwaniaquinone sesquiterpenoid family of natural products is discussed

The Mechanism of Borane–Amine Dehydrocoupling with Bifunctional Ruthenium Catalysts

Borane–amine adducts have received considerable attention, both as vectors for chemical hydrogen storage and as precursors for the synthesis of inorganic materials. Transition metal-catalyzed ammonia–borane (H₃N–BH₃, AB) dehydrocoupling offers, in principle, the possibility of large gravimetric hydrogen release at high rates and the formation of B–N polymers with well-defined microstructure. Several different homogeneous catalysts were reported in the literature. The current mechanistic picture implies that the release of aminoborane (e.g., Ni carbenes and Shvo’s catalyst) results in formation of borazine and 2 equiv of H₂, while 1 equiv of H₂ and polyaminoborane are obtained with catalysts that also couple the dehydroproducts (e.g., Ir and Rh diphosphine and pincer catalysts). However, in comparison with the rapidly growing number of catalysts, the amount of experimental studies that deal with mechanistic details is still limited. Here, we present a comprehensive experimental and theoretical study about the mechanism of AB dehydrocoupling to polyaminoborane with ruthenium amine/amido catalysts, which exhibit particularly high activity. On the basis of kinetics, trapping experiments, polymer characterization by ¹¹B MQMAS solid-state NMR, spectroscopic experiments with model substrates, and density functional theory (DFT) calculations, we propose for the amine catalyst [Ru­(H)₂PMe₃{HN­(CH₂CH₂P<i>t</i>Bu₂)₂}] two mechanistically connected catalytic cycles that account for both metal-mediated substrate dehydrogenation to aminoborane and catalyzed polymer enchainment by formal aminoborane insertion into a H–NH₂BH₃ bond. Kinetic results and polymer characterization also indicate that amido catalyst [Ru­(H)­PMe₃{N­(CH₂CH₂P<i>t</i>Bu₂)₂}] does not undergo the same mechanism as was previously proposed in a theoretical study

High-throughput synthesis provides data for predicting molecular properties and reaction success

Data and code to accompany the publication. Data S1 through S3 are described in the supplementary materials. The virtual library is contained in virtual_library.tar, a tar-archive containing bzip2-compressed CSV files each holding a chunk of 10,000 records for a total of 17,482,092 records. Each record has a unique identifier "mol_number". For each chunk, two files are provided: VL_chunk_xxxx_smiles.csv contains only the identifier and the respective SMILES string. The second file, VL_chunk_xxxx.csv additionally contains the predictions made for the library members. In addition to the identifier and SMILES string, the columns of VL_chunk_xxxx.csv are: - MoKa calculations: [number_of_ionizable_centers, center1_acidorbase, center1_pKa, center1_atom_number, center1_prediction_quality, center2_acidorbase, center2_pKa, center2_atom_number, center2_prediction_quality, center3_acidorbase, center3_pKa, center3_atom_number, center3_prediction_quality, center4_acidorbase, center4_pKa, center4_atom_number, center4_prediction_quality, center5_acidorbase, center5_pKa, center5_atom_number, center5_prediction_quality, center6_acidorbase, center6_pKa, center6_atom_number, center6_prediction_quality, center7_acidorbase, center7_pKa, center7_atom_number, center7_prediction_quality, center8_acidorbase, center8_pKa, center8_atom_number] - Property predictions using Novartis' model: [predicted_logD_pH7.4, predicted_logSolubility_pH6.8_(mM), predicted_ionization_constant] - Property predictions using Schrödinger: [QPlogPo/w, QPlogS]. These are calculated for the all-cis diastereomer. - Reaction outcome predictions for up to two possible reactions leading to the product: [rxn1_smiles, rxn1_predictions, rxn1_confidence, rxn2_smiles, rxn2_predictions, rxn2_confidence