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Ligands, Lewis bases that coordinate to the metal center in a complex, can completely change the catalytic behavior of the metal center. In this Account, we summarize new reactions enabled by a single class of ligands, phosphine-sulfonates (ortho-phosphinobenzenesulfonates). Using their palladium complexes, we have developed four unusual reactions, and three of these have produced novel types of polymers. In one case, we have produced linear high-molecular weight polyethylene, a type of polymer that group 10 metal catalysts do not typically produce. Secondly, complexes using these ligands catalyzed the formation of linear poly(ethylene-co-polar vinyl monomers). Before the use of phosphine-sulfonate catalysts, researchers could only produce ethylene/polar monomer copolymers that have different branched structures rather than linear ones, depending on whether the polymers were produced by a radical polymerization or a group 10 metal catalyzed coordination polymerization. Thirdly, these phosphine-sulfonate catalysts produced nonalternating linear poly(ethylene-co-carbon monoxide). Radical polymerization gives ethylene-rich branched ethylene/CO copolymers copolymers. Prior to the use of phosphine-sulfonates, all of the metal catalyzed processes gave completely alternating ethylene/carbon monoxide copolymers. Finally, we produced poly(polar vinyl monomer-alt-carbon monoxide), a copolymerization of common polar monomers with carbon monoxide that had not been previously reported. Although researchers have often used symmetrical bidentate ligands such as diimines for the polymerization catalysis, phosphine-sulfonates are unsymmetrical, containing two nonequivalent donor units, a neutral phosphine, and an anionic sulfonate. We discuss the features that make this ligand unique. In order to understand all of the new reactions facilitated by this special ligand, we discuss both the steric effect of the bulky phosphines and electronic effects. We provide a unified interpretation of the unique reactivity by considering of the net charge and the enhanced back donation in the phosphine-sulfonate complexes.

Linear polyethylene propagation starting from Pd phosphine-sulfonate complexes, Pd(CH(3))(L)(Ar(2)PC(6)H(4)SO(3)) (L = 2,6-lutidine, Ar = o-MeOC(6)H(4) (2a) and L = pyridine, Ar = Ph (2b)), was studied both experimentally and theoretically. Experimentally, highly linear polyethylene was obtained with Pd(CH(3))(L)(Ar(2)PC(6)H(4)SO(3)) complexes 2a and 2b. Formation of a long alkyl-substituted palladium complex (3) was detected as a result of ethylene oligomerization on a palladium center starting from methylpalladium complex. Additionally, well-defined ethyl and propyl complexes (6(Et) and 6(Pr)) were synthesized as stable n-alkyl palladium complexes. In spite of the existence of beta-hydrogens, the beta-hydride elimination to give 1-alkenes was very slow or negligible in all cases. On the other hand, isomerization of 1-hexene in the presence of a methylpalladium/phosphine-sulfonate complex 2a indicated that this catalyst system actually undergoes beta-hydride elimination and reinsertion to release internal alkenes. On the theoretical side, the relative energies were calculated for intermediates and transition states for chain-growth, chain-walking, and chain-transfer on the basis of the starting model complex Pd(n-C(3)H(7))(pyridine)(o-Me(2)PC(6)H(4)SO(3)) (8). First, cis/trans isomerization process via the Berry's pseudorotation was proposed for the Pd/phosphine-sulfonate system. The second oxygen atom of sulfonate group is involved in the isomerization process as the associative ligand, which is one of the most unique natures of the sulfonate group. Chain propagation was suggested to take place from the less stable alkylPd(ethylene) complex 10' with the TS of 27.4/27.7 ((E+ZPC)/G) kcal/mol. Possible beta-hydride elimination was suggested to occur under low concentration of ethylene: the highest-energy transition state to override for beta-hydride elimination was either >37.4/25.3 kcal/mol (TS(9-12)) or 29.1/27.4 kcal/mol (TS(8'-9') to reach 12'). The ethylene insertion to the iso-alkylpalladium species (14') is allowed via a TS of 28.6/29.1 kcal/mol (TS(14'-15')), slightly higher in energy than that for the normal-alkylpalladium species (TS(10'-11')). Easy chain transfer was suggested to proceed from the more stable PdH(olefin) complex 12' if beta-hydride elimination to 12' does take place. Thus, the production of linear polyethylene with high molecular weight under ethylene pressure suggests that the cis and trans PdH(alkene)(phosphine-sulfonate) complexes (12 and 12') are merely accessible in the presence of excess amount of ethylene.

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Osteocalcin (OC) is a bone-specific protein synthesized by osteoblasts that represents a good marker for osteogenic maturation. We examined whether in vitro osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells (MSCs) could be simply assessed at earlier stages by monitoring OC secretion into the conditioned medium, rather than measuring OC deposition on the extracellular matrix (ECM), using a sandwich enzyme immunoassay system involving a specific anti-rat OC monoclonal antibody. During a 16-day culture, OC was secreted into the medium of MSCs from day 8 and increased substantially until day 16. In contrast, OC deposition on the ECM was low, even at day 13, when calcium deposition was at high levels. The histological expression pattern of OC messenger RNA provided in situ evidence that osteoblastic cells appeared at the early stages of 6 to 9 days and matured over time in vitro. Furthermore, the temporal expression of osteogenesis-specific genes, such as the transcriptional factors core-binding factor 1 and osterix, followed by increases in secretory OC proved the commitment of MSCs to osteoblastic differentiation. These results revealed that biomineralization followed secretion of OC, which may reflect early osteoblastic differentiation of cultured MSCs under osteoinductive conditions. We ascertained the osteogenic differentiation capacity of cultured MSCs in a non-destructive manner by monitoring OC secretion into the culture medium and proved that secretory OC could represent a reliable marker for predicting in vivo osteogenic potential in bone tissue engineering.

Coordination copolymerization of vinyl acetate (VAc) with ethylene, leading to linear copolymers that possess in-chain -CH(2)CH(OAc)- units, has been accomplished using novel palladium complexes bearing alkylphosphine-sulfonate ligands.

We previously reported that in vivo bone formation could be observed in composites of porous hydroxyapatite (HA) scaffolds and cultured mesenchymal stem cells (MSCs). In the present study, we developed a new method for transplantation of cultured MSCs without the necessity of using a scaffold to form bone tissue. MSCs were culture-expanded and lifted as cell sheet structures. These cell sheets, designated osteogenic matrix sheets, showed positive alkaline phosphatase (ALP) staining, high ALP activities and high osteocalcin (OC) contents, indicating their osteogenic potential. We transplanted these sheets into subcutaneous sites in rats to assess whether they possessed in vivo bone-forming capability. The transplanted sheets showed mineralized matrix together with osteocytes and an active osteoblast lining, indicating new bone formation, at 6 weeks after transplantation. HA scaffolds were also wrapped with the sheets to make HA/sheet composites and implanted into subcutaneous sites in rats. Histological sections of the composites revealed bone formation in the HA pores at 4 weeks after implantation. Our present results indicate that MSCs can be cultured as sheet structures, and the resulting sheets themselves or HA-sheet composites represent osteogenic implants that can be used for hard tissue reconstruction.

Dimeric pyrrole-imidazole alkaloids represent a rich and topologically unique class of marine natural products. This full account will follow the progression of efforts that culminated in the enantioselective total syntheses of the most structurally ornate members of this family: the axinellamines, the massadines, and palau’amine. A bio-inspired approach capitalizing on the pseudo-symmetry of the members of this class is recounted, delivering a deschloro derivative of the natural product core. Next, the enantioselective synthesis of the chlorocyclopentane core featuring a scalable, catalytic, enantioselective Diels–Alder reaction of a 1-siloxydiene is outlined in detail. Finally, the successful divergent conversion of this core to each of the aforementioned natural products, and the ensuing methodological developments are described.