Summary Titanium and its alloys have emerged as excellent candidates for use as orthopedic biomaterials. Nevertheless, there are often complications arising after implantation of orthopedic devices, most notably prosthetic joint infection and aseptic loosening. To ensure that implanted devices remain functional in situ , innovation in surface modification has attracted much attention in the effort to develop orthopedic materials with optimal characteristics at the biomaterial-tissue interface. This review will draw together metallurgy, surface engineering, biofilm microbiology, and biomaterial science. It will serve to appreciate why titanium and its alloys are frequently used orthopedic biomaterials and address some of the challenges facing these biomaterials currently, including the significant problem of device-associated infection. Finally, the authors shall consolidate and evaluate surface modification techniques employed to overcome some of these issues by offering a unique perspective as to the direction in which research is headed from a broad, interdisciplinary point of view.

Materials and Methods. Unless stated otherwise, reactions were conducted in flame-dried glassware under an atmosphere of nitrogen using anhydrous solvents (either freshly distilled or passed through activated alumina columns). Chloroform, stabilized with ethanol was stored in the dark over oven-dried 4Å molecular sieves. Methanol and N,N-dimethyl acetamide were used as purchased. 2,2,6-Trimethylcyclohexanone (9) was used as received or prepared according to the procedure reported herein. All other commercially obtained reagents were used as received, unless specified otherwise. IBX was prepared by the method of Santagostino. 1 (S)-t-Bu-PHOX ligand was prepared according to known methods. 2 Reaction temperatures were controlled using an IKAmag temperature modulator. Thin-layer chromatography (TLC) was conducted with E.Merck silica gel 60 F254 pre-coated plates (0.25 mm) and visualized using direct visualization, UV at 254nm or 356nm, p-anisaldehyde, ceric ammonium molybdate, potassium permanganate, and iodine vapor over sand. TLC data include R f , eluent, and method of visualization. ICN silica gel (particle size 0.032-0.063 mm) was used for flash column chromatography. Analytical chiral HPLC analyses were performed with an Agilent 1100 Series HPLC using a chiralcel AD normalphase column (250 x 4.6 mm) employing 0.3-4.0% ethanol in hexane isocratic elution and a flow rate of 0.1 mL/min with visualization at 254nm. Analytical chiral GC analysis was performed with an Agilent 6850 GC using a GT-A column (0.25m x 30.00m) employing an 80°C isotherm and a flow rate of 1.0 mL/min. 1 H NMR spectra were recorded on a Varian Mercury 300 (at 300 MHz) or a Varian Inova 500 (at 500 MHz) and are reported relative to the residual 1 Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64, 4537-4538. Am. Chem. Soc. 2004, 126, 15044-15045.

Pteridinone-based Toll-like receptor 7 (TLR7) agonists were identified as potent and selective alternatives to the previously reported adenine-based agonists, leading to the discovery of GS-9620. Analogues were optimized for the immunomodulatory activity and selectivity versus other TLRs, based on differential induction of key cytokines including interferon α (IFN-α) and tumor necrosis factor α (TNF-α). In addition, physicochemical properties were adjusted to achieve desirable in vivo pharmacokinetic and pharmacodynamic properties. GS-9620 is currently in clinical evaluation for the treatment of chronic hepatitis B (HBV) infection.

α-Quaternary ketones are accessed through novel enantioselective alkylations of allyl and propargyl electrophiles by unstabilized prochiral enolate nucleophiles in the presence of palladium complexes with various phosphinooxazoline (PHOX) ligands. Excellent yields and high enantiomeric excesses are obtained from three classes of enolate precursors: enol carbonates, enol silanes, and racemic β-ketoesters. Each of these substrate classes functions with nearly identical efficiency in terms of yield and enantioselectivity. Catalyst discovery and development, the optimization of reaction conditions, the exploration of reaction scope, and applications in target-directed synthesis are reported. Experimental observations suggest that these alkylation reactions occur through an unusual inner-sphere mechanism involving binding of the prochiral enolate nucleophile directly to the palladium center.