Copper-Catalyst-Controlled Site-Selective Allenylation of Ketones and Aldehydes with Propargyl Boronates

A practical and highly site-selective copper-PhBPE-catalyst-controlled allenylation with propargyl boronates has been developed. The methodology has shown to be tolerant of diverse ketones and aldehydes providing the allenyl adducts in high selectivity. The BPE ligand and boronate substituents were shown to direct the site selectivity for which either propargyl or allenyl adducts can be acquired in high selectivity. A model is proposed that explains the origin of the site selectivity

A Computational Investigation of the Ligand-Controlled Cu-Catalyzed Site-Selective Propargylation and Allenylation of Carbonyl Compounds

A copper-catalyzed site-selective propargylation/allenylation reaction toward carbonyl compounds has been mechanistically investigated using a computational approach. Different reaction pathways and catalytic cycles were investigated. Control of the site selectivity arises from a destabilizing interaction introduced by the phenyl-substituted ligand

General and Rapid Pyrimidine Condensation by Addressing the Rate Limiting Aromatization

The rate limiting aromatization within the condensation approach toward pyrimidines utilizing amidines and activated olefins was addressed to provide for a general and rapid process. A strong solvent effect was elucidated to affect the rate for the initial alkoxide elimination from the intermediate Michael adduct wherein polar aprotic solvents demonstrate an addition controlled aromatization. Spectroscopic studies support a solvent dependent equilibrium between the amidine and alkoxide base wherein the rate for aromatization is optimal when the equilibrium toward the amidine anion was strongly favored

Copper-Catalyzed Asymmetric Propargylation of Cyclic Aldimines

The copper-catalyzed asymmetric propargylation of cyclic aldimines is reported. The influence of the imine trimer to inhibit the reaction was identified, and equilibrium constants between the monomer and trimer were determined for general classes of imines. Asymmetric propargylation of a diverse series of <i>N</i>-alkyl and <i>N</i>-aryl aldimines was achieved with good to high asymmetric induction. The utility was demonstrated by a titanium catalyzed hydroamination and reduction to generate the chiral indolizidines (−)-crispine A and (−)-harmicine

Copper-Catalyzed Asymmetric Propargylation of Cyclic Aldimines

The copper-catalyzed asymmetric propargylation of cyclic aldimines is reported. The influence of the imine trimer to inhibit the reaction was identified, and equilibrium constants between the monomer and trimer were determined for general classes of imines. Asymmetric propargylation of a diverse series of <i>N</i>-alkyl and <i>N</i>-aryl aldimines was achieved with good to high asymmetric induction. The utility was demonstrated by a titanium catalyzed hydroamination and reduction to generate the chiral indolizidines (−)-crispine A and (−)-harmicine

General and Stereoselective Method for the Synthesis of Sterically Congested and Structurally Diverse <i>P</i>‑Stereogenic Secondary Phosphine Oxides

A general and efficient method for the synthesis of bulky and structurally diverse <i>P</i>-stereogenic chiral secondary phosphine oxides (SPOs) by using readily available chiral amino alcohol templates is described. These chiral SPOs could be used as chiral building blocks for the synthesis of difficult-to-access bulky <i>P</i>-stereogenic phosphine compounds or ligands for organic catalysis

Addressing the Configuration Stability of Lithiated Secondary Benzylic Carbamates for the Development of a Noncryogenic Stereospecific Boronate Rearrangement

A practical noncryogenic process for the Aggarwal stereospecific boronate rearrangement with chiral secondary benzylic carbamates has been developed. The use of LDA instead of <i>sec</i>-BuLi combined with an <i>in situ</i> trapping of the unstable lithiated carbamate was critical to success. Furthermore, this new process increased the substrate scope to include the versatile aryl iodide and bromide substrates. The methodology was applied to a diverse array of substrates and was demonstrated on multikilogram scale

Development of New <i>P</i>‑Chiral <i>P</i>,π-Dihydrobenzooxaphosphole Hybrid Ligands for Asymmetric Catalysis

A new family of <i>P</i>-chiral <i>P</i>,π-hybrid ligands was prepared from the dihydrobenzooxaphosphole core. These new ligands were demonstrated to be both sterically and electronically tunable at the substituents on the phosphorus atom <i>and</i> the π-system of the ligand. Application of these new ligands to the catalytic asymmetric addition of boronic acids to imine electrophiles was shown to proceed with high levels of enantioinduction

Development of a ¹³C NMR Chemical Shift Prediction Procedure Using B3LYP/cc-pVDZ and Empirically Derived Systematic Error Correction Terms: A Computational Small Molecule Structure Elucidation Method

An accurate and efficient procedure was developed for performing ¹³C NMR chemical shift calculations employing density functional theory with the gauge invariant atomic orbitals (DFT-GIAO). Benchmarking analysis was carried out, incorporating several density functionals and basis sets commonly used for prediction of ¹³C NMR chemical shifts, from which the B3LYP/cc-pVDZ level of theory was found to provide accurate results at low computational cost. Statistical analyses from a large data set of ¹³C NMR chemical shifts in DMSO are presented with TMS as the calculated reference and with empirical scaling parameters obtained from a linear regression analysis. Systematic errors were observed locally for key functional groups and carbon types, and correction factors were determined. The application of this process and associated correction factors enabled assignment of the correct structures of therapeutically relevant compounds in cases where experimental data yielded inconclusive or ambiguous results. Overall, the use of B3LYP/cc-pVDZ with linear scaling and correction terms affords a powerful and efficient tool for structure elucidation

Hydrophosphination of Propargylic Alcohols and Amines with Phosphine Boranes

The first uncatalyzed hydrophosphinations of propargylic amines and alcohols with phosphine– borane complexes are described. The reactions proceed at ambient temperature or below without the use of protecting groups or the need to handle pyrophoric secondary phosphines, furnishing air-stable phosphineborane–amines and alcohols in good yields. Utilization of chiral propargylic substrates and unsymmetrical secondary phosphineboranes leads to diastereomeric <i>P</i>-chiral products that can be separated by fractional crystallization or chromatography. Initial applications of these new P–X species to asymmetric catalysis are detailed