One-Pot Synthesis of 2,4-Disubstituted Thiazoline from β‑Azido Disulfide and Carboxylic Acid

A concise and efficient one-pot four-step synthesis of 2,4-disubstituted thiazoline via a cascade disulfide bond cleavage/thiocarbonylation/Staudinger reduction/aza-Wittig reaction is established. Treatment of various carboxylic acids with β-azido disulfides under this one-pot procedure obtained the desired thiazolines in good to excellent isolated yields

Total Synthesis of Tetracyclic Spirooxindole Alkaloids via a Double Oxidative Rearrangement/Cyclization Cascade

Skeleton rearrangement could rapidly transfer simple molecules to complex structures and has significant potential in the total synthesis of natural products. We developed a one-pot reaction cascade of double oxidative rearrangement of furan and indole followed by a nucleophilic cyclization that was successfully applied for the formal synthesis of rhynchophylline/isorhynchophylline and the first total synthesis of (±)-7(R)-geissoschizol oxindole/(±)-7(S)-geissoschizol oxindole. In addition, the geissoschizol oxindoles were revised to their C3 epimers, and the mechanism for the reversed stereochemistry through the retro-Mannich/Mannich cascade was proposed and supported by density functional theory calculations

Total Synthesis of Tetracyclic Spirooxindole Alkaloids via a Double Oxidative Rearrangement/Cyclization Cascade

Skeleton rearrangement could rapidly transfer simple molecules to complex structures and has significant potential in the total synthesis of natural products. We developed a one-pot reaction cascade of double oxidative rearrangement of furan and indole followed by a nucleophilic cyclization that was successfully applied for the formal synthesis of rhynchophylline/isorhynchophylline and the first total synthesis of (±)-7(R)-geissoschizol oxindole/(±)-7(S)-geissoschizol oxindole. In addition, the geissoschizol oxindoles were revised to their C3 epimers, and the mechanism for the reversed stereochemistry through the retro-Mannich/Mannich cascade was proposed and supported by density functional theory calculations

Chiral Allene-Containing Phosphines in Asymmetric Catalysis

We demonstrate that allenes, chiral 1,2-dienes, appended with basic functionality can serve as ligands for transition metals. We describe an allene-containing bisphosphine that, when coordinated to Rh(I), promotes the asymmetric addition of arylboronic acids to α-keto esters with high enantioselectivity. Solution and solid-state structural analysis reveals that one olefin of the allene can coordinate to transition metals, generating bi- and tridentate ligands

Chiral Allene-Containing Phosphines in Asymmetric Catalysis

We demonstrate that allenes, chiral 1,2-dienes, appended with basic functionality can serve as ligands for transition metals. We describe an allene-containing bisphosphine that, when coordinated to Rh(I), promotes the asymmetric addition of arylboronic acids to α-keto esters with high enantioselectivity. Solution and solid-state structural analysis reveals that one olefin of the allene can coordinate to transition metals, generating bi- and tridentate ligands

Chiral Allene-Containing Phosphines in Asymmetric Catalysis

We demonstrate that allenes, chiral 1,2-dienes, appended with basic functionality can serve as ligands for transition metals. We describe an allene-containing bisphosphine that, when coordinated to Rh(I), promotes the asymmetric addition of arylboronic acids to α-keto esters with high enantioselectivity. Solution and solid-state structural analysis reveals that one olefin of the allene can coordinate to transition metals, generating bi- and tridentate ligands

Chiral Allene-Containing Phosphines in Asymmetric Catalysis

We demonstrate that allenes, chiral 1,2-dienes, appended with basic functionality can serve as ligands for transition metals. We describe an allene-containing bisphosphine that, when coordinated to Rh(I), promotes the asymmetric addition of arylboronic acids to α-keto esters with high enantioselectivity. Solution and solid-state structural analysis reveals that one olefin of the allene can coordinate to transition metals, generating bi- and tridentate ligands

In Silico Identification of a Novel Hinge-Binding Scaffold for Kinase Inhibitor Discovery

To explore novel kinase hinge-binding scaffolds, we carried out structure-based virtual screening against p38α MAPK as a model system. With the assistance of developed kinase-specific structural filters, we identify a novel lead compound that selectively inhibits a panel of kinases with threonine as the gatekeeper residue, including BTK and LCK. These kinases play important roles in lymphocyte activation, which encouraged us to design novel kinase inhibitors as drug candidates for ameliorating inflammatory diseases and cancers. Therefore, we chemically modified our substituted triazole-class lead compound to improve the binding affinity and selectivity via a “minimal decoration” strategy, which resulted in potent and selective kinase inhibitors against LCK (18 nM) and BTK (8 nM). Subsequent crystallographic experiments validated our design. These rationally designed compounds exhibit potent on-target inhibition against BTK in B cells or LCK in T cells, respectively. Our work demonstrates that structure-based virtual screening can be applied to facilitate the development of novel chemical entities in crowded chemical space in the field of kinase inhibitor discovery

Development of Dihydroxyphenyl Sulfonylisoindoline Derivatives as Liver-Targeting Pyruvate Dehydrogenase Kinase Inhibitors

Pyruvate dehydrogenase kinases 1–4 (PDK1–4) negatively control activity of the pyruvate dehydrogenase complex (PDC) and are up-regulated in obesity, diabetes, heart failure, and cancer. We reported earlier two novel pan-PDK inhibitors PS8 [4-((5-hydroxyisoindolin-2-yl)­sulfonyl)­benzene-1,3-diol] (<b>1</b>) and PS10 [2-((2,4-dihydroxyphenyl)­sulfonyl)­isoindoline-4,6-diol] (<b>2</b>) that targeted the ATP-binding pocket in PDKs. Here, we developed a new generation of PDK inhibitors by extending the dihydroxyphenyl sulfonylisoindoline scaffold in <b>1</b> and <b>2</b> to the entrance region of the ATP-binding pocket in PDK2. The lead inhibitor (<i>S</i>)-3-amino-4-(4-((2-((2,4-dihydroxyphenyl)­sulfonyl)­isoindolin-5-yl)­amino)­piperidin-1-yl)-4-oxobutanamide (<b>17</b>) shows a ∼8-fold lower IC₅₀ (58 nM) than <b>2</b> (456 nM). In the crystal structure, the asparagine moiety in <b>17</b> provides additional interactions with Glu-262 from PDK2. Treatment of diet-induced obese mice with <b>17</b> resulted in significant liver-specific augmentation of PDC activity, accompanied by improved glucose tolerance and drastically reduced hepatic steatosis. These findings support <b>17</b> as a potential glucose-lowering therapeutic targeting liver for obesity and type 2 diabetes