Solution-phase synthesis design

Hulme C, Chappeta S, Griffith C, Lee YS, Dietrich J (2009) An efficient solution phase synthesis of triazadibenzoazulenones designer isonitrile free methodology enabled by microwaves. Tetrahedron Lett 50 1939-1942... 

Human recombinant Factor Vila Complex tissue factor/factor Vila ligands designed to bind to the Gla-domain in Factor Vila. Solid-phase combinatorial chemistry solution-phase synthesis of a sub-library Affinity chromatography SPR 7,15 ... 

Scaffold proposals were collected and reviewed according to privileged ion channel motifs, chemical feasibility, and fit to our multiple pharmacophores. Building block selection, virtual library design, and filtering yielded small virtual libraries suitable for automated solution-phase synthesis. All synthesized compounds were finally purified and characterized prior to addition to our focused library. 

Parallel organic synthesis can be performed both on a solid phase and in solution. Obviously, solid-phase synthesis is less difficult to automate as work-up usually consists only of simple filtration steps. Solution-phase synthesis often requires automation of work-up procedures such as liquid-liquid extraction or isolation and purification of intermediates. Strategies and devices designed for automating both solution- and solid-phase synthesis are dealt vdth in this chapter. 

Low-cost reaction blocks primarily designed for solution-phase synthesis are, for example, manufactured by Zinsser and Scigene (Table 2, Fig. 3). 

The possibility to run reactions in a homogeneous fashion is one of the attractive features of solution phase synthesis techniques over the conceptually related solid phase synthesis techniques. However, the incorporation of fluorous chains to permit molecules to partition into a fluorous phase naturally begins to alter the solubility properties of the resulting fluorinated organic molecules. Indeed, molecules with very large fluorous domains can have little or no solubility in many common organic solvents. Thus, solubility and selection of a reaction solvent are crucial considerations in designing fluorous reactions or reactions sequences. 

Combinatorial chemistry has played a highly visible role in the drug discovery effort in several companies numerous new companies have been set up to partner established companies in the discovery of new molecular entities. Dr. Ian Hughes reviews the state of the art with selected examples from his own research at Glaxo Smith KJine. This is followed by an excellent exposition by Drs. Norton Peet and Hwa-Ok Kim regarding efficient design and development of parallel solution-phase synthesis. 

A particularly convenient feature of this technique, by contrast with solution-phase synthesis, is that there is no need for multistep purification of the product because the by-products and debris are easily washed away from the solid support before proceeding to the next coupling cycle with a new amino acid. The solid support can be reacted with reagents in various types of apparatus it can be simply held in a tube sandwiched between porous frits whilst reagents are pumped past, or reagents can be injected into and sucked out of vials sealed with a rubber septum, or it can be treated in 96-well plate format blocks of miniature reactors. There are also several proprietory styles of solid support designed for convenience of use. 

The synthetic 21-amino acid polypeptide KL4 [(KL4)4K] was developed as a pulmonary surfactant to be used in treatment of respiratory distress syndrome (RDS) in infants (IRDS) and in adults (ARDS). KL4 is designed to contain intermittent hydrophobic (Leucine) and hydrophilic (Lysine) regions to mimic the structure of the natural surfactant protein B (SP-B). The solution phase synthesis of KL4 is a challenging task. The protection and deprotection patterns, the possibility of diastereomer formation in every coupling step, the solubility (or lack of it) of the different fragments and the isolation of intermediates are among the potential problems that face such a synthesis. The process research work resulted in a successful and efficient large scale synthesis of KL4 which will be discussed. 

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