Kevin D. Bunker

Design of Potent and Selective Inhibitors to Overcome Clinical Anaplastic Lymphoma Kinase Mutations Resistant to Crizotinib.

Crizotinib (1), an anaplastic lymphoma kinase (ALK) receptor tyrosine kinase inhibitor approved by the U.S. Food and Drug Administration in 2011, is efficacious in ALK and ROS positive patients. Under pressure of crizotinib treatment, point mutations arise in the kinase domain of ALK, resulting in resistance and progressive disease. The successful application of both structure-based and lipophilic-efficiency-focused drug design resulted in aminopyridine 8e, which was potent across a broad panel of engineered ALK mutant cell lines and showed suitable preclinical pharmacokinetics and robust tumor growth inhibition in a crizotinib-resistant cell line (H3122-L1196M).

Scalable synthesis of 1-bicyclo[1.1.1]pentylamine via a hydrohydrazination reaction.

The reaction of [1.1.1]propellane with di-tert-butyl azodicarboxylate and phenylsilane in the presence of Mn(dpm)(3) to give di-tert-butyl 1-(bicyclo[1.1.1]pentan-1-yl)hydrazine-1,2-dicarboxylate is described. Subsequent deprotection gives 1-bicyclo[1.1.1]pentylhydrazine followed by reduction to give 1-bicyclo[1.1.1]pentylamine. The reported route marks a significant improvement over the previous syntheses of 1-bicyclo[1.1.1]pentylamine in terms of scalability, yield, safety, and cost.

Reactions of a Metallacyclobutene Complex with Alkenes

The first productive reactions of a characterized metallacyclobutene complex with alkenes are reported. Thus, the metallacyclobutene complex (eta5-C5H5)(PPh3)Co[kappa2-(C,C)-C(SO2Ph) C(Si(CH3)3)CH(CO2CH2CH3)] (2) undergoes reaction with alkenes to give 1,4-diene complexes with a high degree of regio- and stereoselectivity. A mechanism is proposed in which the metallacyclobutene generates a cyclic vinylcarbene intermediate that undergoes [4 + 2]-cycloaddition reactions with activated alkenes. A model of the vinylcarbene intermediate has been examined using quantum mechanical methods.

Thermolysis of [(η5-C5H5)Co(PPh3)(η2-DMAD)], revisited: a solid state analysis reveals the true structure of the triphenylphosphine–alkyne coupling product

Abstract Thermolysis of the η 2 -alkyne complex (η 5 -C 5 H 5 )Co(PPh 3 )[η 2 -(MeO 2 C)CC(CO 2 Me)] ( 1 -DMAD) leads to formation of an ortho -metalated vinyl-phosphonium derivative (η 5 -C 5 H 5 )Co[η 2 -(MeO 2 C)HCC(CO 2 Me)PPh 2 (η 1 - o -C 6 H 4 )] ( 4 ) as well as a small amount of the tricobalt bis(carbyne) cluster [(η 5 -C 5 H 5 )Co] 3 [μ 3 ,η 3 -C(CO 2 Me)] 2 ( 3 -CO 2 Me). Thermolysis of 1 -DMAD in the presence of added triphenylphosphine gives 4 as the major product, with no evidence for formation of 3 -CO 2 Me. Complexes 4 and 3 -CO 2 Me were characterized by X-ray crystallographic analyses.

Ring-strain effects on the oxidation potential of enediynes and enediyne complexes

The metal-enediyne complexes [(eta 5-C5H5)Fe[eta 5-1,2-C5H3C identical to C(CH2)nC identical to]] (4, n = 4; 5, n = 5) and [(eta 5-C5H5)-Fe[eta 5-1,2-C5H3(C identical to C Me)2]] (6) were prepared from 1,2-diethynylferrocene (3). Complexes 4 and 5 were characterized in the solid state by X-ray crystallographic analysis. The structures of 4 and 6 were determined by computation using ab initio methods. A correlation was observed between ring-strain and increased ease of electrochemical oxidation along the series 6 (+0.164 V) to 5(+0.152 V) to 4 (+0.123 V). A similar trend in ionization potentials was identified in both the gas phase and in solution by computational methods.

2-Chloro-4-(1H-pyrazol-1-yl)-5-(trifluoro-meth-yl)pyrimidine.

The reaction of 2,4-dichloro-5-(trifluoromethyl)pyrimidine with 1H-pyrazole gave two structural isomers in a 1:1 ratio that were separable by chromatography. The title compound, C8H4ClF3N4, was the first product to elute and was characterized in the present study to confirm that substitution by the pyrazolyl group had occurred at position 4. The molecule (with the exception of the F atoms) is essentially planar, with a mean deviation of 0.034 Å from the least-squares plane through all non-H and non-F atoms. The bond angles in the pyrimidine ring show a pronounced alternating pattern with three angles, including those at the two N atoms being narrower, and the remaining three wider than 120°.

4-Chloro-7-hydr­oxy-6-methyl-1,7-naphthyridin-8(7H)-one

The title compound, C9H7ClN2O2, was prepared by reaction of methyl 4-chloro-3-(prop-1-ynyl)picolinate with hydroxylamine in MeOH/KOH solution. The two essentially planar molecules which make up the asymmetric unit have almost identical geometries and and are linked into dimeric aggregates via pairs of O—H⋯O hydrogen bonds. These aggregates have almost perfect inversion symmetry; however, quite unusually, the inversion center of the dimer does not coincide with the crystallographic inversion center.

3-Amino-5-bromo-2-iodo-pyridine.

The reaction of 3-amino-5-bromopyridine with N-iodosuccinimide in the presence of acetic acid produces the title compound, C5H4BrIN, with an iodo substituent in position 2 of the pyridine ring. The crystal structure features rather weak intermolecular N—H⋯N hydrogen bonds linking the molecules into chains along the z axis of the crystal.