PPAR, Non-Selective

Ligand 4 is a deep purple solid and has a limited solubility profile due to its planarity and thus recrystallization from refluxing ethanol was used to purify this compound

Ligand 4 is a deep purple solid and has a limited solubility profile due to its planarity and thus recrystallization from refluxing ethanol was used to purify this compound.10 Open in a separate window Scheme 1 Reagents and conditions: (a) Pd(dba)2 (10%), PPh3 (20%), Na2CO3 (3.1 equiv), THF:H2O (5:1), 75 C, 7 hrs (70%). dimens ional space. Following this strategy we disclosed over the last two years a series of simple ruthenium-based protein kinase inhibitors such as 1 which mimic the overall shape of the family of indolocarbazole alkaloids (e.g., staurosporine, see Figure 1).3 Almost all our compounds include the pyridocarbazole ligand 2 as a key pharmacophore which substitutes for the indolocarbazole aglycone 3 of staurosporine. The heterocycle 2 serves as a very strong bidentate ligand in ruthenium complexes. Additional ligands in the Mouse monoclonal to CHUK coordination sphere of the metal substitute for the carbohydrate moiety of staurosporine, with the metal center serving as a glue to unite all of the parts. This approach has resulted in the successful design of nanomolar and even picomolar Benzyl benzoate protein kinase inhib itors.1 Open in a separate window Figure 1 Staurosporine as a lead structure for the design of ruthenium-based protein kinase inhibitors. We became interested in designing ruthenium complexes with similar overall structure but modulated electron density at the metal center. This may allow us to design kinase inhibitors with additional functions such as luminescence, reactivity, or catalytic properties, which generally depend on the electronic nature of all involved ligands. Towards this goal we here disclose the synthesis of em N /em -benzyl pyrido[3,2- em e /em ]-2,10b-diaza-cyclopenta[ em c /em ]fluorene-1,3-dione 4, which differs from the pyridocarbazole 2 scaffold by the connectivity of the indole moiety. This heterocycle can serve as a bidentate ligand for ruthenium as demonstrated for the complex 5, forming a coordinative bond with the pyridine and a covalent bond with a carbon of the indole moiety. The synthesis of heterocycle 4 is an overall six step route (Scheme 1). Michael addition/elimination of indoline 6 with em N /em -benzyl dibromomaleimide 7 followed by DDQ oxidation afforded the cross coupling partner 8 according to a published procedure.4 A Pd-mediated Suzuki cross coupling6 reaction in THF:H2O (5:1) with commercially-available boronic acid 95 (1.5 equiv) afforded the disubstituted maleimide 10 in 70% yield.7 It was important in this reaction to first reflux a solution of the substrates/reagents in THF prior to addition of H2O, otherwise intractable precipitation of the catalyst occurred upon heating. The reaction did not proceed, however, without H2O which is necessary to dissolve the base. Removal of the methyl group of 10 with BBr3 resulted in decomposition of the starting material but instead demethylation under milder conditions with NaI/TBDMSCl in MeCN gave the pyridone 11 in a high yield of 95%.8 Formation of the triflate 12 was achieved with 2.0 equiv of Tf2O in pyridine.9 This choice of solvent is necessary to avoid formation of low-yielding mixtures of O- and N-triflates. An intramolecular Pd-catalyzed Heck reaction6 was the final key step in the synthesis of ligand 4.10 Table 1 outlines a variety of conditions used to optimize this intramolecular cyclization. An initial stoichiometric C-C bond formation with Pd(OAc)2 led only to decomposition of the starting material (Entry 1). Subsequent catalytic couplings with Pd(dba)2 or PdCl2(PPh3)2 gave no cyclization product either (Entries 2 and 3). Further couplings with Pd(PPh3)4 plus KOAc as a base (Entry 4) and Pd2(dba)3 plus Et3N (Entry 5) gave the desired cyclization product in modest yields of 23% and 44%, respectively. We finally found that the combination of the electron rich Pd(0) catalyst Pd(PPh3)4 in combination with 3.1 equiv Et3N affords quantitative yields of the Heck coupling product 4 (Entry 6). Thus, the right reaction conditions are highly critical Benzyl benzoate for this intramolecular Heck coupling to occur in high yields. Ligand 4 is a deep purple solid and has a limited solubility profile due to its planarity and thus recrystallization from refluxing ethanol was used to purify this compound.10 Open in a separate window Scheme 1 Reagents and conditions: Benzyl benzoate (a) Pd(dba)2 (10%), PPh3 (20%), Na2CO3 (3.1 equiv), THF:H2O (5:1), 75 C, 7 hrs (70%). (b) TBDMSCl (3 equiv), NaI (4 equiv), MeCN, 0 C to RT, 12 hrs (95%). (c) Tf2O (2 equiv), pyridine, 0 C to RT, 1 hr (75%). (d) Pd(PPh3)4 (20%), Et3N (3.1 equiv), DMF, 85 C, 15 hrs (100%). (e) [CpRu(CO)(MeCN)2]+PF6- (1.5 equiv), Et3N (1.2 equiv), DMF, 55 C, 2 hrs (61%). Table 1 Optimization of the intramolecular Heck coupling with 12 thead th align=”center” valign=”middle” rowspan=”1″ colspan=”1″ Entry /th th align=”center” valign=”middle” rowspan=”1″ colspan=”1″ Catalyst /th th align=”center” valign=”middle” rowspan=”1″ colspan=”1″ Base /th th align=”center” valign=”middle” rowspan=”1″ colspan=”1″ Ligandb /th th align=”center” valign=”middle” rowspan=”1″ colspan=”1″ Solvent /th th Benzyl benzoate align=”center” valign=”middle” rowspan=”1″ colspan=”1″ Temp (C) /th th align=”center” valign=”middle” rowspan=”1″ colspan=”1″ Yields (%) /th /thead 1Pd(OAc)2 (1.0 equiv)NaOAc (2.0 equiv)PPh3 (2.0 equiv) Bu4NI (1.0 equiv)Dioxane8502Pd(dba)2a (0.05 equiv)Et3N (3.0 equiv)dppp (0.06 equiv)DMF8503PdCl2(PPh3)2 (0.1.