New Diphosphine Ligands Based on Heterocyclic Aromatics Inducing Very High Regioselectivity in Rhodium-Catalyzed Hydroformylation: Effect of the Bite Angle

Kranenburg, Mirko; Burgt, Yuri E. M. van der; Kamer, P.C.J.; Leeuwen, Piet W. N. M. van; Goubitz, K.; Fraanje, Jan

doi:10.1021/om00006a057

Cited by 867 publications

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“…8 Installation of functionality at C7 was accomplished by displacement of the 7-chloro group in 5,7-dichloro-3-cyano-pyrazolo[1,5-a]pyrimidine (4) to afford intermediates of general structure 5. Substitution at C5 was subsequently achieved by palladium catalyzed 10 or KFpromoted coupling of 5 with the requisite N-(3-aminoaryl)-acetamide (6) to furnish the desired analogues (7a−l).…”

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confidence: 99%

Structure and Property Based Design of Pyrazolo[1,5-a]pyrimidine Inhibitors of CK2 Kinase with Activity in Vivo

Dowling

Alimzhanov

Bao

et al. 2013

ACS Med. Chem. Lett.

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In this letter, we describe the design, synthesis, and structure−activity relationship of 5-anilinopyrazolo [1,5-a]pyrimidine inhibitors of CK2 kinase. Property-based optimization of early leads using the 7-oxetan-3-yl amino group led to a series of matched molecular pairs with lower lipophilicity, decreased affinity for human plasma proteins, and reduced binding to the hERG ion channel. Agents in this study were shown to modulate pAKT S129 , a direct substrate of CK2, in vitro and in vivo, and exhibited tumor growth inhibition when administered orally in a murine DLD-1 xenograft. KEYWORDS: CK2 kinase, pyrazolo[1,5-a]pyrimidine, matched molecular pair, oxetane T he serine/threonine protein kinase CK2, a tetrameric complex containing two catalytic (α or α′) and two regulatory (β) subunits, controls cell growth, proliferation, and evasion of apoptosis by phosphorylation of a range of substrates in critical cellular signaling pathways including PI3K (phosphatidylinositol 3-kinase)/AKT (protein kinase B), NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) and Wnt (wingless type MMTV integration site family).1−3 Overexpression of the CK2α subunit correlates with tumor aggressiveness and disease severity in certain cancers, while compensatory increases in CK2α′ levels have been observed in response to RNAi treatment in mice.4,5 Several academic and industrial research groups have been actively engaged in developing small molecule inhibitors of CK2 to provide further pharmacological validation of the compelling in vitro and in vivo data amassed to date. 6 The recent discovery of CX-4945, a selective, orally available inhibitor of CK2 by researchers from Cylene, represents an important first step in evaluating the clinical potential of this novel target in man. 7 We have recently described the design of a series of conformationally constrained inhibitors of CK2 containing the pyrazolo[1,5-a]pyrimidine nucleus.8 Members of this series of compounds exhibited potent inhibition of the enzyme, possessed a high degree of kinase selectivity, and depleted cellular levels of pAKT S129 , a direct substrate of CK2 believed to hyperactivate the AKT pathway.9 Although our attempts to enhance both cellular potency and physical properties in this series were unsuccessful, these studies resulted in an understanding of the structure−property relationships within the scaffold and provided additional insights into ligand−receptor binding. In particular, we found that N-methylation of the acetamide of 1a, to give ring-constrained analogue 1b, preserved enzymatic and cellular activity. In subsequent designs, we proposed to release the constraint in 1b and introduce a new conformational constraint, exemplified by indoline 2, that would enforce the crystallographically observed cisoid conformation of the acetamide in 1 (Figure 1). Compound 2 is a potent inhibitor

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confidence: 99%

Structure and Property Based Design of Pyrazolo[1,5-a]pyrimidine Inhibitors of CK2 Kinase with Activity in Vivo

Dowling

Alimzhanov

Bao

et al. 2013

ACS Med. Chem. Lett.

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“…12 These backbones provide a unique combination of rigidity and P-P distance in such a way, that specific, large bite-angle coordination modes are supported. Additionally interaction of the central oxygen atom in the backbone with a metal atom coordinated is possible under certain conditions.…”

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confidence: 99%

Coordination chemistry and X-ray studies with novel sterically constrained diphosphonite ligands

et al. 2003

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The coordination of two novel, sterically constrained diphosphonite ligands towards different palladium, platinum and rhodium precursors has been studied. Complexes of this hitherto unexplored class of diphosphonites, based on rigid xanthene backbones, have been characterized by X-ray crystallography as well as by NMR and IR spectroscopy. A short and concise overview is given on the scarce literature on phosphonite related chemistry. Structural differences in the complexes obtained due to steric influences of the ligands are discussed. Ligand 1, bearing 2-tert-butylphenolate groups, led to orthometallated complexes cis-[MCl{1-κ 3 C,P,P}] (M = Pd, Pt) and to trans- [RhCl(CO) (1)]. These complexes were compared with those formed with ligand 2, bearing 2,2Ј-dioxo-3,3Ј-di-tert-butyl-5,5Ј-dimethoxy-1,1Ј-biphenyl groups, preventing orthometallation. The complexes trans-{PdCl 2 (2)], cis-[PtCl 2 (2)] and trans-[RhCl(CO)(2)] were structurally characterized. Valuable data were collected on chemical shifts, Pt-P coupling constants, as well as CO stretch frequencies of Rh-CO complexes as important tools for structural characterization of such complexes. IntroductionProgress and development of homogeneous catalysis is very much related and dependent on the synthesis and availability of ligands. In recent years a number of powerful new ligand classes have emerged, most of which are chelating phosphorusbased compounds 1 such as phosphines 2 or phosphites.3 Phosphonites however have been widely neglected and only very recently a few examples were reported. Reetz et al. used several backbones, amongst others ferrocene, to prepare chelating diphosphonites and used them in asymmetric Rh-catalyzed hydrogenations of the typical benchmark substrates 4 as well as in conjugate addition of aryl boronic acids.5 ZanottiGerosa et al. also described diphosphonites but they used the para-cyclophane backbone and performed hydrogenation reactions.6 Pringle andco-workers used binaphthol-derived mono-and bidentate phosphonites for conjugate additions of diethyl zinc to enones. 7 The same monophosphonites were used by Claver and Pringle in asymmetric hydrogenations.8 Scharf and co-workers used the monodentate phosphonites based on TADDOL as the chiral auxiliary for the rhodum-catalyzed hydrosilylation of ketones.9 Börner and co-workers have published on the use of both monodentate and bidentate phosphonite ligands in the hydroformylation of alkenes, with varying results.10 Finally the Reetz group, in line with their earlier work, prepared phosphite-phosphonite bidentate ligands but no applications in catalysis were reported so far. 11During recent years xanthene-based chelating ligands have been introduced and extensively used in transition metal catalyzed C-C bond forming reactions.12 These backbones provide a unique combination of rigidity and P-P distance in such a way, that specific, large bite-angle coordination modes are supported. Additionally interaction of the central oxygen atom in the backbone with a metal atom coordinated is possible...

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“…Both compounds have been characterized by correct NMR ( 1 H, 13 C, 31 P) and 13 C, 31 P) and mass-spectroscopic data, by satisfactory elemental analysis data and by single-crystal X-ray structure analysis (see Scheme 3).…”

Section: Resultsmentioning

confidence: 99%

“…Thus, trans-[PdCl 2 (SPANphos)] reported by van Leeuwen does not show any tendency to cis-trans isomerization [10], the complex trans-[PdCl 2 (diphos)] (diphos = 2,6-bis(2-((diphenylphosphino)methyl)phenyl)benzene) reported by Protasiewicz [11] has been successfully used as Heck and Suzuki catalyst, in spite of the rigid trans-geometry [12]. With the diphosphine Xantphos, developed by van Leeuwen [13] and used as a ligand for Suzuki reactions, palladium complexes with trans-standing alkyl and chloro ligands [14] and with trans-standing aryl and bromo ligands [15] have been isolated and characterized by X-ray crystallography.…”

Section: Introductionmentioning

confidence: 99%

Square-planar dichloro palladium complexes with trans-configurated phosphine ligands avoiding ortho-metallation: Ligand design, complex synthesis, molecular structure and catalytic potential for Suzuki cross-coupling reactions

Chahen

Therrien

Süß‐Fink

2006

Journal of Organometallic Chemistry

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The square-planar palladium complexes trans-[PdCl 2 (PPh 2 -CH 2 -2,4,6-C 6 H 2 Me 3 ) 2 ] (1) and trans-[PdCl 2 (g 2 -PPh 2 -CH 2 -2,4,6-C 6 HMe 3 -CH 2 -2,4,6-C 6 HMe 3 -CH 2 -PPh 2 )] (2) have been synthesized from [PdCl 2 (cod)] (cod = 1,5-cyclooctadiene) and the corresponding new phosphine or diphosphine ligands. The single-crystal X-ray structure analysis reveals for both complexes a trans arrangement of the two chlorine and of the two phosphorus atoms. In both cases, ortho-metallation leading to palladacycles is not possible, since all ortho positions in the benzylic rings of 1 and 2 are blocked by methyl substituents. Both complexes are found to catalyze Suzuki cross-coupling reactions of deactivated and even bulky arene substrates.

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New Diphosphine Ligands Based on Heterocyclic Aromatics Inducing Very High Regioselectivity in Rhodium-Catalyzed Hydroformylation: Effect of the Bite Angle

Cited by 867 publications

References 1 publication

Structure and Property Based Design of Pyrazolo[1,5-a]pyrimidine Inhibitors of CK2 Kinase with Activity in Vivo

Structure and Property Based Design of Pyrazolo[1,5-a]pyrimidine Inhibitors of CK2 Kinase with Activity in Vivo

Coordination chemistry and X-ray studies with novel sterically constrained diphosphonite ligands

Square-planar dichloro palladium complexes with trans-configurated phosphine ligands avoiding ortho-metallation: Ligand design, complex synthesis, molecular structure and catalytic potential for Suzuki cross-coupling reactions

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