Chiral tertiary alcohols are important building blocks for the synthesis of pharmaceutical agents and biologically active natural products. The addition of carbon nucleophiles to ketones is the most common approach to tertiary alcohol synthesis, but traditionally relies on stoichiometric organometallic reagents that are difficult to prepare, sensitive, and uneconomical. We describe a mild and efficient method for the copper-catalyzed allylation of ketones, using widely available 1,3-dienes as allylmetal surrogates. Homoallylic alcohols bearing a wide range of functional groups are obtained in high yield and with good regio-, diastereo-, and enantioselectivity. Mechanistic investigations using density functional theory (DFT) implicate the in situ formation of a rapidly equilibrating mixture of isomeric copper(I) allyl complexes, from which Curtin-Hammett kinetics determine the major isomer of product. A stereochemical model is provided to explain the high diastereo-and enantioselectivity of this process. Finally, this method was applied toward the preparation of an important drug, (R)-Procyclidine, and a key intermediate in the synthesis of several pharmaceuticals.

The Rh(I)-catalyzed allenic Pauson-Khand reaction (APKR) is an efficient, redox-neutral method of synthesizing α-acyloxy cyclopentenones. An enantioselective APKR could provide access to chiral, nonracemic α-acyloxy and α-hydroxy cyclopentenones and their corresponding redox derivatives, such as thapsigargin, a cytotoxic natural product with potent antitumor activity. Rapid scrambling of axial chirality of allenyl acetates in the presence of Rh(I) catalysts enables the conversion of racemic allene to enantiopure cyclopentenone product in a dynamic kinetic asymmetric transformation (DyKAT). A combined experimental and computational approach was taken to develop an effective catalytic system to achieve the asymmetric transformation. The optimization of the denticity, and steric and electronic properties of the ancillary ligand (initially (S)-MonoPhos, 58:42 er), afforded a hemilabile bidentate (S)-MonoPhos-alkene-Rh(I) catalyst that provided α-acyloxy cyclopentenone product in up to 14:86 er. Enantioselectivity of the Rh(I)-(S)-MonoPhos-alkene catalyst was rationalized using ligand-substrate steric interactions and distortion energies in the computed transition states. This asymmetric APKR of allenyl acetates is a rare example of a Type I DyKAT reaction of an allene, the first example of DyKAT in a cyclocarbonylation reaction, and the first catalyst-controlled enantioselective APKR.

<p>Chiral tertiary alcohols are important building blocks for the synthesis of pharmaceutical agents and biologically active natural products. The addition of carbon nucleophiles to ketones is the most common approach to tertiary alcohol synthesis, but traditionally relies on stoichiometric organometallic reagents that are difficult to prepare, sensitive, and uneconomical. We describe a mild and efficient method for the copper-catalyzed allylation of ketones, using widely available 1,3-dienes as allylmetal surrogates. Homoallylic alcohols bearing a wide range of functional groups are obtained in high yield and with good regio-, diastereo-, and enantioselectivity. Mechanistic investigations using density functional theory (DFT) implicate the in situ formation of a rapidly equilibrating mixture of isomeric copper(I) allyl complexes, from which Curtin-Hammett kinetics determine the major isomer of product. A stereochemical model is provided to explain the high diastereo- and enantioselectivity of this process. Finally, this method was applied toward the preparation of an important drug, (R)-Procyclidine, and a key intermediate in the synthesis of several pharmaceuticals.</p> <br>

Herein, we describe an efficient method to prepare polysubstituted pyrroles via a copper-hydride (CuH)-catalyzed enyne-nitrile coupling reaction. This protocol accommodates both aromatic and aliphatic substituents and a broad range of functional groups, providing a variety of N-H pyrroles in good yields and with high regioselectivity. We propose that the Cu-based catalyst promotes both the initial reductive coupling and subsequent cyclization steps. Density functional theory (DFT) calculations were performed to elucidate the reaction mechanism.

The narrow substrate scope of the asymmetric Pauson–Khand reaction (PKR) presently limits its synthetic utility. We recently reported an example of an enantioselective PKR with a precursor not comprising a 1,6-enyne by using a cationic Rh­(I) catalyst and a chiral monodentate phosphorous ligand. Herein, the mechanisms and ligand effects on the reactivity and selectivity of enyne PKRs using Rh­(I) metal complexes with three different ligands ((R)-BINAP, (S)-MonoPhos, or CO) are examined experimentally and computationally. A correlation between experiments and DFT calculations is demonstrated. The PKR with the bidentate ligand (R)-BINAP is fast and shows a low calculated Gibbs free energy of activation (ΔG ‡) for the oxidative cyclization step; the monodentate ligand, (S)-MonoPhos, affords a much slower reaction with a higher ΔG ‡; and using the CO-only Rh complex, the reaction is very slow with a high ΔG ‡. A linear relationship between the enantiomeric excess of (S)-MonoPhos and the PKR product suggests that the active Rh catalyst involves a single ligand. The absolute configuration of the product afforded by each of these ligand-bound catalysts is determined by DFT calculations and confirmed by vibrational circular dichroism spectroscopy. Transition-state structures for the oxidative cyclization step show that the chiral induction is controlled by steric interactions between the phenyl groups of the (R)-BINAP ligand or the methyl groups of the (S)-MonoPhos ligand and an alkenyl hydrogen of the enyne. DFT calculations revealed two competing oxidative cyclization pathways involving either four- or five-coordinated Rh­(I) species. The preferred mechanism and the enantioselectivity are affected by the ligand, the substrate, and CO concentration. Incorporating experimental temperature and CO concentration into the Gibbs free-energy calculations proved crucial for obtaining agreement with experimental results.