A new route for the synthesis of 2-aminopyridines has been developed that merges C–H functionalization with amide alcoholysis. The key component of this method is the ability of a quinazolinone to template the chemo- and regioselective construction of a latent pyridine ring via site-selective olefinic C–H bond functionalization under Ru(II) catalysis. Thus, highly substituted 2-aminopyridines were prepared in good yield. Mechanistic studies provide insight into the mechanism of the key oxidative C–H activation/annulation process.
Tautomerizable heteroarenes, bearing multiple interconvertible nucleophilic centers exhibit high chemo- and regio- selective allylation irrespective of allylating agents used under Pd-catalysis. The achieved selectivity may be attributed to the dominant lactam form of heteroarenes and Pd-catalyzed intramolecular allylic substitution. A generalized green protocol for chemo- and regio-selective allylation of biologically relevant heteroarenes with allyl alcohols in dimethyl carbonate (DMC) as solvent was developed. Excellent selectivity was observed during intermolecular competition study demonstrating the differential nucleophilicity of tautomerizable heteroarenes and differential allyl palladium forming ability of a variety of allyl alcohols.
“Highly chemo- and regioselective allylic substitution with tautomerizable heteroarenes
Dinesh Kumar, Sandeep R. Vemula, Gregory R. Cook*
Green Chemistry 2015, accepted for publication
An unprecedent improvement in the reaction rate (from hours to minutes) was observed during the In-mediated allylation of isatins with allyl bromide in the presence of N-Boc-glycine. The observed phenomena was generalized as a general protocol for the allylation of differently substituted isatins with excellent yields in a short time and with a wide range of functional group tolerance. Evidence suggests the unique role of the N-Boc-glycine additive was to increase the rate of formation and increase the nucleophilicity of the allylindium organometallic reagent.
“N-Boc-glycine-assisted indium-mediated allylation reaction: A sustainable approach”
Sandeep Reddy Vemula, Dinesh Kumar, and Gregory R. Cook*
Tetrahedron Lett. 2015, 56, accepted for publication
special edition in honor of Prof. Harry Wasserman
The general and efficient palladium-catalyzed indium-mediated allylation of chiral hydrazones was accomplished with excellent yield (72-92%) and diastereoselectivity (up to 99:1). The development of this reaction as well as substrate scope is described. Conversion was found to be proportional to phosphine concentration, which provided insight into the mechanism and competing pathways of the redox transmetalation process.
“Highly Diastereoselective Palladium-Catalyzed Indium-Mediated Allylation of Chiral Hydrazones”
Narayanaganesh Balasubramanian, Tanmay Mandal, and Gregory R. Cook,*
Organic Letters 2015, 17, accepted for publication
Of different histone deacetylase (HDAC) isozymes, HDAC8 is a highly malleable enzyme, and it exhibits the potential to accommodate structurally diverse ligands (albeit with moderate binding affinities) in its active site pocket. To probe the molecular basis of this feature, we performed the detailed thermodynamic studies for the binding of structurally similar ligands, which differed with respect to the “cap”, “linker”, and “metal-binding” regions of the Suberoylanilide Hydroxamic Acid (SAHA) pharmacophore, to HDAC8. The experimental data revealed that although the enthalpic (ΔH°) and entropic (ΔS°) changes for the binding of individual SAHA analogues to HDAC8 were substantially different, their binding free energies (ΔG°) were markedly similar, conforming to a strong enthalpy-entropy compensation effect. The enthalpy-entropy compensation effect was further observed in the temperature-dependent binding thermodynamics of all SAHA analogues to the enzyme. On the other hand, the magnitude of the proton inventory, intrinsic enthalpy, and the heat capacity changes (ΔCp°) associated with the ligand binding to HDAC8 markedly differed from one SAHA analogue to the other, and such features could only be rationalized in the light of the dynamic flexibility in the enzyme structure in conjunction with the organization of the active site resident water molecules. Arguments are presented that although the above binding thermodynamic features would facilitate identification of weak to moderately tight binding HDAC8 inhibitors (by a high throughput and/or virtual screening of the library of small molecules), they would pose major challenges in the structure-based rational design of highly potent and isozyme-selective inhibitors of HDAC8.
“Binding Thermodynamics of Structurally Similar Ligands to Histone Deacetylase 8 Sheds Light on Challenges in Rational Design of Potent and Isozyme-selective Inhibitors of the Enzyme”
Raushan K Singh , Takayoshi Suzuki , Tanmay Mandal , Narayanaganesh Balsubramanian , Manas K Haldar , Dustin J. Mueller , Jerrod A. Strode , Gregory Cook , Sanku Mallik , and D. K. Srivastava
Biochemistry – Accepted for publication