A bisphosphonite calix[5]arene ligand that stabilizes η6 arene coordination to palladium.

Treatment of a bis(phenylphosphonite)calix[5]arene ligand with either palladium(II) chloride or 1,5-cyclooctadieneplatinum(II) chloride yields square planar metal complexes in which the two phosphorus atoms bind cis to the MCl(2) moiety (M = Pd, Pt). Chloride was removed from the palladium complex to open a coordination site at the metal for catalysis. The chloride removal resulted in a rare and unexpected η(6) coordination of an arene to the metal. The reaction is reversible upon addition of tetra-n-butyl ammonium chloride.

Synthesis and characterization of AP5346, a novel polymer-linked diaminocyclohexyl platinum chemotherapeutic agent.

Syntheses of the novel polymer-bound platinum-based chemotherapeutic agent poly(HPMA)-GGG-Ama=Pt=(1R,2R)-DACH, AP5346, and its precursors are reported. The method utilized in preclinical development of AP5346 is described herein. Additionally, an improved synthesis, which has shown that ion exchange resins can be removed, significantly less platinum can be used when the reaction mixture is pH-stated, and the synthesis can be performed at a higher concentration, is reported. These combined improvements result in a more cost-effective, scaleable procedure. Various methods of analysis of the drug substance are also discussed. Specifically, (1)H NMR spectroscopy is used for identity and can also distinguish small molecule impurities to below 0.1%. (195)Pt NMR determines the coordination environment of the platinum and also identity and purity in relation to platinum chelation of the construct. Size exclusion chromatography is used to establish the molecular weight of AP5346 while ICP-AES determines platinum content and platinum release rates in phosphate-buffered saline. The cumulative results of this work have yielded an efficient syntheses of a polymer-based chemotherapeutic agent with subsequent detailed characterization methods.

Phosphorus-based p-tert-butylcalix[5]arene ligands.

New calix[5]arene trivalent phosphorus derivatives have been synthesized which should be excellent ligands with which to study and control the interaction of a ligand atom with a metal. The larger cavity of the calix[5]arene (compared to calix[4]arene) provides a good balance between constraint and flexibility. Treatment of p-tert-butylcalix[5]arene with 2 equiv of either tris(dimethylamino)phosphine or dichlorophenylphosphine inserts two RP moieties into the calix[5]arene framework to give calix[5](PR)2(OH) (1, R = Me2N; 2, R = Ph). Further treatment of 1 with 4 equiv of HCl gives calix[5](PCl)2(OH) (3). Heating a solution of the monophosphorus compound calix[5](PNMe2)(OH)3 (4) releases dimethylamine to yield both monomeric calix[5](P)(OH)2 (6) and dimeric [calix[5](P)(OH)2](2) (7), the latter having a tubelike geometry. X-ray crystallographic studies confirm the structures and show that 1 and 2 have approximate cone conformations while 3 has an approximate 1,2-alternate conformation. The orientations of the phosphorus lone pairs and oxygen atoms in all derivatives provide a framework for both soft and hard ligand interactions within the calix[5]arene.

Chloro- and Fluoro-Substituted Phosphites, Phosphates, and Phosphoranes Exhibiting Sulfur and Oxygen Coordination(1).

New cyclic phosphoranes, O(2)S[Me(t-Bu)C(6)H(2)O](2)PCl(3) (1), O(2)S[Me(t-Bu)C(6)H(2)O](2)P(OC(6)H(4)-m-CF(3))(3) (2), and O(2)S[(t-Bu)(2)C(6)H(2)O](2)PCl(3) (3), containing sulfone donor groups and halogen substituents were synthesized by oxidative addition reactions of a diol with a tricoordinated phosphorus precursor. Cyclic phosphates, O(2)S[(t-Bu)(2)C(6)H(2)O](2)P(O)Cl (4) and O(2)S[Me(t-Bu)C(6)H(2)O](2)P(O)(OC(6)H(4)-m-CF(3)) (5), resulted from hydrolysis reactions of 3 and 2, respectively. Phosphate O(2)S[Me(t-Bu)C(6)H(2)O](2)P(O)(OC(6)F(5)) (6) was prepared from a known phosphorane precursor and independently from the reaction of an N-oxide molecule with a parent phosphite, O(2)S[Me(t-Bu)C(6)H(2)O](2)P(OC(6)F(5)). Two additional compounds containing a sulfur atom in place of the sulfone group, a cyclic phosphite, S[Me(2)C(6)H(2)O](2)P(OC(6)F(5)) (7), and a cyclic phosphate, S[Me(2)C(6)H(2)O](2)P(O)Cl (8), were synthesized. X-ray analysis and NMR data were obtained on all of these compounds to establish the role of electronegative ligands in promoting donor interaction. Compounds 1-3 were hexacoordinate as a consequence of oxygen atom coordination while 7 and 8 were trigonal bipyramidal due to sulfur atom coordination. The chlorine atom and the pentafluorophenoxy group promote similar degrees of coordination in these compounds. The results support the conclusion that the sulfur atom and oxygen atom of the sulfone group show similar coordination abilities in donor action with phosphoranes containing strongly electronegative ligands while in the presence of less electronegative ligands sulfur is the stronger coordinating agent. With phosphates and phosphites the sulfur atom exerts the stronger donor action independent of the electronegativity of the attached ligands.

Structure-Reactivity Relationships for Associative Displacement Reactions of Penta- and Hexacoordinate Cyclic Oxyphosphoranes with Catechols(1)(,)(2).

The reactivity of a series of cyclic pentaoxyphosphoranes containing a sulfonyl group was carried out, O(2)S[(t-Bu)MeC(6)H(2)O](2)P(OCH(2)CF(3))(3) (1), O(2)S[(t-Bu)MeC(6)H(2)O](2)P(OPh)(3) (2), O(2)S[(t-Bu)(2)C(6)H(2)O](2)P(OCH(2)CF(3))(3) (4), and O(2)S[(t-Bu)(2)C(6)H(2)O](2)P(OPh)(3) (5). Also included were derivatives containing sulfur, S[(t-Bu)MeC(6)H(2)O](2)P(OPh)(3) (6) and S[(t-Bu)(2)C(6)H(2)O](2)P(OPh)(3) (8), and the methylene group, CH(2)[(t-Bu)MeC(6)H(2)O](2)P(OPh)(3) (7), in place of the sulfonyl group in the ring-containing component. (31)P NMR monitoring of the reactions of the oxyphosphoranes with catechol and 4-nitrocatechol shows the following order of reactivity: 7 > 8 > 6 > 2 > 5 >> 1. It is established that the reactions are associative. An analysis of the products formed is given relative to this mechanistic process. Both 1 and 4 are found to be inert toward nucleophilic displacement by the catechols employed. It is suggested that the looseness of P-O bonds (implied by their increased length) that reside in either octahedral formulations or in axial positions of a trigonal biyramid is the principal factor associated with reactivity for these cyclic oxyphosphoranes. For the hexacoordinated geometries, the order of reactivity parallels the extent of octahedral character: 8 > 6 > 2 > 5.

Increased Coordination via Sulfur Donor Action in Cyclic Pentaoxyphosphoranes and the Parent Cyclic Phosphite. Influence of Pentafluorophenoxy Ligands(1).

The pentafluorophenoxy ligand was introduced into the new cyclic pentaoxyphosphoranes S[(t-Bu)MeC(6)H(2)O](2)P(OC(6)F(5))(O(2)C(6)Cl(4)) (1), S[(t-Bu)MeC(6)H(2)O](2)P(OC(6)F(5))(O(2)C(14)H(8)) (2), and S[(t-Bu)MeC(6)H(2)O](2)P(OC(6)F(5))(3) (3). X-ray analysis revealed hexacoordinate structures formed by sulfur donor action present as a bridging atom in flexible eight-membered rings for 1-3. X-ray analysis showed that sulfur coordination also occurred with the same type of ring system as part of the phosphite S[(t-Bu)MeC(6)H(2)O](2)P(OC(6)F(5)) (4) to give a pseudo-trigonal-bipyramidal geometry. The pentafluorophenoxy ligand present in the oxyphosphoranes 1-3 as well as in the phosphite 4 acts comparably to a chlorine atom in its ability to enhance phosphorus electrophilicity as measured by the degree of P-S coordination and geometrical displacement toward a more highly coordinated state. The phosphite 4 has a P-S donor distance of 2.876(2) Å, considerably longer than the range of P-S distances from 2.366(3) to 2.495(2) Å obtained for the pentaoxyphosphoranes 1-3. These data express quantitatively the relative electrophilicity of phosphorus as a function of coordination number and substituent composition.

Hexacoordination via Sulfur Donor Action in Bicyclic Pentaoxyphosphoranes(1).

New bicyclic oxyphosphoranes, S[(t-Bu)MeC(6)H(2)O](2)P(OC(6)H(5))(O(2)C(6)H(3)F) (1) and S[(t-Bu)MeC(6)H(2)O](2)P(OC(6)H(5))(O(2)C(6)H(4)) (3), were synthesized by displacement reactions of a monocyclic pentaoxyphosphorane by a diol, and S[(t-Bu)(2)C(6)H(2)O](2)P(OCH(2)CF(3))(O(2)C(6)Cl(4)) (2) and S[(t-Bu)(2)C(6)H(2)O](2)P(C(6)H(5))(O(2)C(6)Cl(4)) (4), by oxidative addition reactions of a phosphite or phosphine with tetrachlorobenzoquinone. X-ray studies revealed hexacoordinated structures formed by the presence of a sulfur donor atom incorporated in a flexible eight-membered ring. The structures were displaced along a coordinate from a square pyramid toward an octahedron. (31)P and (1)H NMR data are also reported. Comparisons are made between bicyclic tetraoxyphosphoranes and monocyclic and bicyclic pentaoxyphosphoranes which show the importance of ligand electronegativity in increasing the degree of hexacoordination. Of the various series now studied, the extent of sulfur donor atom coordination increases in the following order: phosphates < phosphites < oxyphosphoranes. It is concluded that, in general, sulfur donor atom coordination will take place with phosphorus in any of the common coordination geometries in the presence of sufficiently electronegative ligands.