19 research outputs found
Pd-catalyzed enantioselective aerobic oxidation of secondary alcohols: Applications to the total synthesis of alkaloids
Enantioselective syntheses of the alkaloids (-)-aurantioclavine, (+)-amurensinine, (-)-lobeline, and (-)- and (+)-sedamine are described. The syntheses demonstrate the effectiveness of the Pd-catalyzed asymmetric oxidation of secondary alcohols in diverse contexts and the ability of this methodology to set the absolute configuration of multiple stereocenters in a single operation. The utility of an aryne C-C insertion reaction in accessing complex polycyclic frameworks is also described
Enantioselective Synthesis of Caprolactam and Enone Precursors to the Heterocyclic DEFG Ring System of Zoanthenol
The enantioselective synthesis of both caprolactam and enone synthons for the DEFG ring system of zoanthenol are described. The evolution of this approach proceeds first through a synthesis using the chiral pool as a starting point. Challenges in protecting-group strategy led to the modification of this approach beginning with (±)-glycidol. Ultimately, an efficient approach was developed by employing an asymmetric hetero-Diels–Alder reaction. The caprolactam building block can be converted by an interesting selective Grignard addition into the corresponding enone synthon. Addition of a model alkyne provides support for the late-stage addition of a hindered alkyne to the caprolactam building block
Palladium-Catalyzed Enantioselective Oxidation of Alcohols: A Dramatic Rate Acceleration by Cs_2CO_3/t-BuOH
The addition of Cs_2CO_3 and t-BuOH provides a dramatic rate acceleration in the palladium-catalyzed aerobic oxidative kinetic resolution of secondary alcohols while maintaining the selectivity of the process
Palladium-Catalyzed Enantioselective Oxidation of Alcohols: A Dramatic Rate Acceleration by Cs_2CO_3/t-BuOH
The addition of Cs_2CO_3 and t-BuOH provides a dramatic rate acceleration in the palladium-catalyzed aerobic oxidative kinetic resolution of secondary alcohols while maintaining the selectivity of the process
The Palladium-Catalyzed Aerobic Kinetic Resolution of Secondary Alcohols: Reaction Development, Scope, and Applications
The first palladium-catalyzed enantioselective oxidation of secondary alcohols has been developed, utilizing the readily available diamine (-)-sparteine as a chiral ligand and molecular oxygen as the stoichiometric oxidant. Mechanistic insights regarding the role of the base and hydrogen-bond donors have resulted in several improvements to the original system. Namely, addition of cesium carbonate and tert-butyl alcohol greatly enhances reaction rates, promoting rapid resolutions. The use of chloroform as solvent allows the use of ambient air as the terminal oxidant at 23 °C, resulting in enhanced catalyst selectivity. These improved reaction conditions have permitted the successful kinetic resolution of benzylic, allylic, and cyclopropyl secondary alcohols to high enantiomeric excess with good-to-excellent selectivity factors. This catalyst system has also been applied to the desymmetrization of meso-diols, providing high yields of enantioenriched hydroxyketones
Palladium-Catalyzed Oxidative Kinetic Resolution with Ambient Air as the Stoichiometric Oxidation Gas
Air is enough to mediate the highly enantioselective oxidation of secondary alcohols at room temperature with palladium(II) and sparteine in nonflammable solvents. Examination of the role of solvents capable of hydrogen bonding and their ability to solvate halide anions led to a novel set of conditions for the highly enantioselective oxidative kinetic resolution of secondary alcohols
Effect of Chirality on Common in Vitro Experiments: An Enantiomeric Pair Analysis
This
analysis elucidates the impact of small molecule architecture
on common in vitro ADME assays. In vitro parameters considered in
this analysis included Caco-2 permeability/efflux, CYP3A4 inhibition,
hERG inhibition, and rat microsomal extraction ratio (ER). The statistical
significance and practical meaningfulness of chirality were determined
by comparison of the distribution of enantiomers with the experimental
variation distribution observed from duplicate measurements. Statistical
tools were applied to characterize the role of molecular architecture
on the outcome of a given in vitro assay. We found that CYP3A4 inhibition,
hERG inhibition, Caco-2 permeability, and efflux are unlikely to be
modulated by chirality. However, rat microsomal ER provides a statistically
significant, <i>and quantitatively meaningful</i>, chance
of being influenced by chirality
Optimization of Fused Bicyclic Allosteric SHP2 Inhibitors
SHP2 is a nonreceptor protein tyrosine phosphatase within the mitogen-activated protein kinase (MAPK) pathway controlling cell growth, differentiation, and oncogenic transformation. SHP2 also participates in the programed cell death pathway (PD-1/PD-L1) governing immune surveillance. Small-molecule inhibition of SHP2 has been widely investigated, including in our previous reports describing SHP099 (2), which binds to a tunnel-like allosteric binding site. To broaden our approach to allosteric inhibition of SHP2, we conducted additional hit finding, evaluation, and structure-based scaffold morphing. These studies, reported here in the first of two papers, led to the identification of multiple 5,6-fused bicyclic scaffolds that bind to the same allosteric tunnel as 2. We demonstrate the structural diversity permitted by the tunnel pharmacophore and culminated in the identification of pyrazolopyrimidinones (e.g., SHP389, 1) that modulate MAPK signaling in vivo. These studies also served as the basis for further scaffold morphing and optimization, detailed in the following manuscript