7 research outputs found
A General Strategy for Organocatalytic Activation of C–H Bonds via Photoredox Catalysis: Direct Arylation of Benzylic Ethers
Direct C–H functionalization
and arylation of benzyl ethers
has been accomplished via photoredox organocatalysis. The productive
merger of a thiol catalyst and a commercially available iridium photoredox
catalyst in the presence of household light directly affords benzylic
arylation products in good to excellent yield. The utility of this
methodology is further demonstrated in direct arylation of 2,5-dihydrofuran
to form a single regioisomer
Aza-Morita−Baylis−Hillman Reactions and Cyclizations of Conjugated Dienes Activated by Sulfone, Ester, and Keto Groups
Protocol for the Direct Conversion of Lactones to Lactams Mediated by 1,5,7-Triazabicyclo[4.4.0]dec-5-ene: Synthesis of Pyridopyrazine-1,6-diones
We present an operationally
simple lactone-to-lactam transformation
utilizing diverse amine nucleophiles. The key steps of amidation,
alcohol activation, and cyclization are all mediated by one reagent
(TBD) in a single vessel at room temperature. We illustrate the convenience
of this protocol by synthesizing a wide range of <i>N</i>-alkyl, <i>N</i>-aryl, and <i>N</i>-hetereoaryl
pyridopyrazine-1,6-diones, an important class of medicinally significant
lactams. Furthermore, the reported methodology can be applied to the
synthesis of milligram to hundred gram quantities of pyridopyrazine-1,6-diones
without the use of specialized equipment
Ru/Ni Dual Catalytic Desulfinative Photoredox C<sub>sp<sup>2</sup></sub>–C<sub>sp<sup>3</sup></sub> Cross‑Coupling of Alkyl Sulfinate Salts and Aryl Halides
A mild Ru/Ni dual
catalytic desulfinative photoredox C<sub>sp<sup>2</sup></sub>–C<sub>sp<sup>3</sup></sub> cross-coupling reaction
of alkyl sulfinate salts with aryl halides has been developed. The
optimized catalyst system, consisting of RuÂ(bpy)<sub>3</sub>Cl<sub>2</sub>, NiÂ(COD)<sub>2</sub>, and DBU, smoothly mediates the coupling
of a diverse set of secondary and primary nonactivated alkyl sulfinate
salts with a broad range of electron-deficient aryl bromides, electron-rich
aryl iodides, and heteroaryl bromides under irradiation with blue
light. The procedure is ideal for late-stage introduction of alkyl
groups on pharmaceutical intermediates, and the C<sub>sp<sup>2</sup></sub>–C<sub>sp<sup>3</sup></sub> cross-coupling reaction
allowed the rapid synthesis of caseine kinase 1δ inhibitor analogues
via a parallel medicinal chemistry effort
Discovery of cyclopropyl chromane-derived pyridopyrazine-1,6-dione γ-secretase modulators with robust central efficacy††Electronic supplementary information (ESI) available. CCDC 1452774. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6md00406g
γ-Secretase modulators for the treatment of Alzheimer's disease.
Herein we describe the discovery of a novel series of cyclopropyl chromane-derived pyridopyrazine-1,6-dione γ-secretase modulators for the treatment of Alzheimer's disease (AD). Using ligand-based design tactics such as conformational analysis and molecular modeling, a cyclopropyl chromane unit was identified as a suitable heterocyclic replacement for a naphthyl moiety that was present in the preliminary lead
4
. The optimized lead molecule
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achieved good central exposure resulting in robust and sustained reduction of brain amyloid-β42 (Aβ42) when dosed orally at 10 mg kg
–1
in a rat time-course study. Application of the unpaced isolated heart Langendorff model enabled efficient differentiation of compounds with respect to cardiovascular safety, highlighting how minor structural changes can greatly impact the safety profile within a series of compounds