Development of a Modified System to Provide Improved Diastereocontrol in the Linear-Selective Cu-Catalyzed Reductive Coupling of Ketones and Allenamides.

Chiral γ-lactones are prevalent organic architectures found in a large array of natural products. In this work, we disclose the development of a modified catalytic system utilizing a commercially available Cu-phosphite catalyst for the diastereoselective reductive coupling of chiral allenamides and ketones to afford chiral γ-lactone precursors in 80:20 to 99:1 dr.

Bis(benzoyl) phosphate inactivators of beta-lactamase C from Mtb.

The class A ß-lactamase BlaC is a cell surface expressed serine hydrolase of Mycobacterium tuberculosis (Mtb), one of the causative agents for Tuberculosis in humans. Mtb has demonstrated increased susceptibility to ß-lactam antibiotics upon inactivation of BlaC; thus, making BlaC a rational enzyme target for therapeutic agents. Herein, we present the synthesis and structure-activity-relationship data for the 1st-generation library of bis(benzoyl) phosphates (1-10). Substituent effects ranged from σp = -0.27 to 0.78 for electronic and π = -0.41 to 1.98 for hydrophobic parameters. Compounds 1, 4 and 5 demonstrated the greatest inhibitory potency against BlaC in a time-dependent manner (kobs = 0.212, 0.324, and 0.450 mn-1 respectively). Combined crystal structure data and mass spectrometric analysis of a tryptic digest for BlaC inactivated with 4 provided evidence that the mechanism of inactivation by this bis(benzoyl) phosphate scaffold occurs via phosphorylation of the active-site Ser-70, ultimately leading to an aged form of the enzyme.

Asymmetric Access to Boryl-Substituted Vicinal Aminoalcohols through Cu-Catalyzed Reductive Coupling.

Herein, we report the development of a Cu-catalyzed enantioselective borylative aminoallylation of aldehydes using a N-substituted allene to access boryl-substituted 1,2-aminoalcohol synthons for diversification to chiral heteroatom-rich organic compounds. The reported reaction provides access to several different substitution patterns of chiral 1,2-aminoalcohol products from the same readily available starting materials with high diastereo- and enantioselectivity.

Access to a Catalytically Generated Umpolung Reagent through the Use of Cu-Catalyzed Reductive Coupling of Ketones and Allenes for the Synthesis of Chiral Vicinal Aminoalcohol Synthons.

We report the development of a stereoselective method for the allylation of ketones utilizing N-substituted allyl equivalents generated from a chiral allenamide. By employing N-heterocyclic carbenes as ligands for the Cu catalyst, good branched selectivity can be obtained with high diastereocontrol. This methodology allows access to a catalytically generated, polarity-reversed (umpolung) allyl nucleophile to enable the preparation of chiral 1,2-aminoalcohol synthons containing a dissonant functional group relationship.

Development of a Strategy for Linear-Selective Cu-Catalyzed Reductive Coupling of Ketones and Allenes for the Synthesis of Chiral γ-Hydroxyaldehyde Equivalents.

We report the development of a stereoselective method for the allylation of ketones utilizing N-substituted allyl equivalents generated from a chiral allenamide. By choice of the appropriate ligand for the Cu-catalyst, high linear selectivity can be obtained with good diastereocontrol. This methodology allows access to chiral γ-hydroxyaldehyde equivalents that were applied in the synthesis of chiral γ-lactones and 2,5-disubstitued tetrahydrofurans.