Regiospecific Acylation of Cycloplatinated Complexes: Scope, Limitations, and Mechanistic Implications

A series of platinum complexes based on the tridentate cyclometalating ligand derivatives 6-arylamino-2,2′-bipyridine, 6-phenoxy-2,2′-bipyridine, 6-phenylthio-2,2′-bipyridine, 6-benzyl-2,2′-bipyridine, and 6-benzoyl-2,2′-bipyridine were synthesized, and their acylation reactions were studied. Acylation of platinum complexes based on 6-(4-R-phenylamino)-2,2′-bipyridine derivatives (R = CH₃O, CH₃, Cl, COOEt) tolerates both electron-donating and electron-withdrawing substituents on the aryl ring that are para to the amino group. However, platinum complexes based on 6-(3-R′-phenylamino)-2,2′-bipyridine (R′ = CH₃, Cl, Br) did not undergo the acylation reaction under the same conditions. Interestingly, the acylation of the platinum complexes based on 6-(3-fluorophenylamino)-2,2′-bipyridine proceeded smoothly, and the results indicate that the acylation is regiospecific and occurs at the metalated carbon. Complexes based on 6-phenoxy-2,2′-bipyridine, 6-phenylthio-2,2′-bipyridine, and 6-benzyl-2,2′-bipyridine are also regioselectively acylated. A cyclometalated platinum complex based on 6-benzoyl-2,2′-bipyridine, where the benzene is more electron deficient than those in other cyclometalated platinum complexes, failed to undergo the acylation reaction. The acylation can be carried out in acetic acid, 1,2-dichloroethane, benzonitrile, and acetonitrile. Other acyl halides such as benzoyl chloride and crotonyl chloride are also effective acylating reagents. On the basis of the fact that the reaction is discouraged by the electron deficiency of the phenyl ring and contrasting results of the acylation of platinum complexes based on 6-(3-R′-phenylamino)-2,2′-bipyridine (R′ = CH₃, F, Cl, Br), an unprecedented electrophilic addition–platinum migration–rearomatization cascade mechanism is proposed for the regiospecific acylation reaction

Computational and Experimental Study on Selective sp²/sp³ or Vinylic/Aryl Carbon–Hydrogen Bond Activation by Platinum(II): Geometries and Relative Stability of Isomeric Cycloplatinated Compounds

Cyclometalating ligands 6-(1-phenylethyl)-2,2′-bipyridine (<b>L4</b>), 6-(1-phenylvinyl)-2,2′-bipyridine (<b>L5</b>), and 6-(prop-1-en-2-yl)-2,2′-bipyridine (<b>L6</b>) were synthesized by the Negishi coupling of 6-bromo-2,2′-bipyridine with the corresponding organozinc reagents. The reaction of <b>L4</b> with K₂PtCl₄ produced only the cycloplatinated compound <b>4a</b> via sp² C–H bond activation. The reactions of <b>L5</b> and <b>L6</b> produced exclusively the cycloplatinated compounds <b>5b</b> and <b>6a</b>, respectively, via vinylic C–H bond activation. DFT calculations were performed on 12 possible cycloplatination products from the reaction of <i>N</i>-alkyl-<i>N</i>-phenyl-2,2′-bipyridin-6-amine (alkyl = methyl (<b>L1</b>), ethyl (<b>L2</b>), and isopropyl (<b>L3</b>)) and <b>L4</b>–<b>L6</b>. The results show that compounds <b>1b</b>–<b>3b</b> resulting from the sp³ C–H bond activation of <b>L1</b>–<b>L3</b> are thermodynamic products, and their relative stability is attributed to the planar geometry that allows for a better conjugation. Similar reasoning also applies to the stability of products from vinylic C–H bond activation of <b>L5</b> and <b>L6</b>. The relative stability of isomeric cycloplatinated compounds <b>4a</b> and <b>4b</b> may be due to the different strengths of C–Pt bonds. The steric interaction is the major cause of severe distortion from a planar coordination geometry in the cycloplatinated compounds, which leads to instability of the corresponding cyclometalated products and a higher kinetic barrier for C–H bond activation

Computational and Experimental Study on Selective sp²/sp³ or Vinylic/Aryl Carbon–Hydrogen Bond Activation by Platinum(II): Geometries and Relative Stability of Isomeric Cycloplatinated Compounds

Cyclometalating ligands 6-(1-phenylethyl)-2,2′-bipyridine (<b>L4</b>), 6-(1-phenylvinyl)-2,2′-bipyridine (<b>L5</b>), and 6-(prop-1-en-2-yl)-2,2′-bipyridine (<b>L6</b>) were synthesized by the Negishi coupling of 6-bromo-2,2′-bipyridine with the corresponding organozinc reagents. The reaction of <b>L4</b> with K₂PtCl₄ produced only the cycloplatinated compound <b>4a</b> via sp² C–H bond activation. The reactions of <b>L5</b> and <b>L6</b> produced exclusively the cycloplatinated compounds <b>5b</b> and <b>6a</b>, respectively, via vinylic C–H bond activation. DFT calculations were performed on 12 possible cycloplatination products from the reaction of <i>N</i>-alkyl-<i>N</i>-phenyl-2,2′-bipyridin-6-amine (alkyl = methyl (<b>L1</b>), ethyl (<b>L2</b>), and isopropyl (<b>L3</b>)) and <b>L4</b>–<b>L6</b>. The results show that compounds <b>1b</b>–<b>3b</b> resulting from the sp³ C–H bond activation of <b>L1</b>–<b>L3</b> are thermodynamic products, and their relative stability is attributed to the planar geometry that allows for a better conjugation. Similar reasoning also applies to the stability of products from vinylic C–H bond activation of <b>L5</b> and <b>L6</b>. The relative stability of isomeric cycloplatinated compounds <b>4a</b> and <b>4b</b> may be due to the different strengths of C–Pt bonds. The steric interaction is the major cause of severe distortion from a planar coordination geometry in the cycloplatinated compounds, which leads to instability of the corresponding cyclometalated products and a higher kinetic barrier for C–H bond activation

Reaction of <i>N</i>‑Isopropyl‑<i>N</i>‑phenyl-2,2′-bipyridin-6-amine with K₂PtCl₄: Selective C–H Bond Activation, C–N Bond Cleavage, and Selective Acylation

The selective C–H bond activation of <i>N</i>-isopropyl-<i>N</i>-phenyl-2,2′-bipyridin-6-amine promoted by Pt­(II) was complicated by the low selectivity of sp² C–H bond activation in acetonitrile and low yield of sp³ C–H activation in acetic acid. The use of a base was found to effectively suppress the competing sp³ C–H bond activation in acetonitrile, improving the selectivity of sp² C–H bond activation from 70% to 99%. In the reaction in acetic acid, the low yield was due to the competing C–N bond cleavage. The use of a base reduced the C–N bond cleavage, but not completely. The reaction of <i>N</i>-<i>tert</i>-butyl-<i>N</i>-phenyl-2,2′-bipyridin-6-amine with K₂PtCl₄ in acetic acid produced the cyclometalated complex with complete C–N bond cleavage and its acylated derivative. These results indicated that the C–N bond cleavage might proceed via heterolytic C–N bond dissociation. The acylation following the C–N cleavage in the reaction in acetic acid is regioselective. Further experiments showed that the reaction of <i>N</i>-phenyl-2,2′-bipyridin-6-amine with K₂PtCl₄ in acetic acid produced the cyclometalated complex, while the reaction in a mixture of acetic anhydride and acetic acid produced the acylated cyclometalated complex. An X-ray crystal structure study revealed strong intramolecular H bonding in the acylated complexes. The regioselectivity was explained in terms of H bonding and the electron distribution predicted by the DFT calculations

Discovery of a Potent and Selective Sphingosine Kinase 1 Inhibitor through the Molecular Combination of Chemotype-Distinct Screening Hits

Sphingosine kinase (SphK) is the major source of the lipid mediator and G protein-coupled receptor agonist sphingosine-1-phosphate (S1P). S1P promotes cell growth, survival, and migration and is a key regulator of lymphocyte trafficking. Inhibition of S1P signaling has been proposed as a strategy for treatment of inflammatory diseases and cancer. Two different formats of an enzyme-based high-throughput screen yielded two attractive chemotypes capable of inhibiting S1P formation in cells. The molecular combination of these screening hits led to compound <b>22a</b> (PF-543) with 2 orders of magnitude improved potency. Compound <b>22a</b> inhibited SphK1 with an IC₅₀ of 2 nM and was more than 100-fold selective for SphK1 over the SphK2 isoform. Through the modification of tail-region substituents, the specificity of inhibition for SphK1 and SphK2 could be modulated, yielding SphK1-selective, potent SphK1/2 dual, or SphK2-preferential inhibitors