Solid-phase synthesis optimization

In aqueous DMF, the reaction can be applied to the formation of C-C bonds in a solid-phase synthesis with resin-bound iodobenzoates (Eq. 6.33).80 The reaction proceeds smoothly and leads to moderate to high yield of product under mild conditions. The optimal conditions involve the use of 9 1 mixture of DMF-water. Parsons investigated the viability of the aqueous Heck reactions under superheated conditions.81 A series of aromatic halides were coupled with styrenes under these conditions. The reaction proceeded to approximately the same degree at 400°C as at 260°C. Some 1,2-substituted alkanes can be used as alkene equivalents for the high-temperature Heck-type reaction in water.82... 

NA Sole, G Barany. Optimization of solid-phase synthesis of [Ala8]-dynorphin A1 3, (scavenger Reagents B, K, R) J Org Chem 57, 5399, 1992. 

S Kates, NA Sole, M Beyermann, G Barany, F Albericio. Optimized preparation of deca(L-alanyl)-L-valinamide by 9-fluorenylmethoxyloxycarbonyl (Fmoc) solid-phase synthesis on polyethylene glycol-polystyrene (PEG-PS) graft supports, with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) deprotection. Pept Res 9, 106, 1996. 

Other fields using short monolithic units are solid phase synthesis and combinatorial chemistry. Hird et al. [102] predicted that having a single polymer particulate block of porous polymer or monolith would allow the optimization of automation in the field of solid phase (combinatorial) synthesis. They have developed a method for the preparation of monolithic rods, which were then cut into discs of 1.0 to 2.5 mm thickness and used for solid phase synthesis. They... 

Dragovich, P. S., Zhou, R., Skalitzky, D. J., Fuhrman, S. A., Patick, A. K., Ford, . E., Meador, J. W., Ill, Worland, S. T. (1999) Solid-phase synthesis of irreversible human rhinovirus 3C protease inhibitors. Part 1 optimization of tripeptides incorporating N-terminal amides. Bioorg Med Chem 7, 589-598. 

In an interesting application of a gaseous reagent to solid-phase synthesis, Takahashi and co-workers demonstrated hydroformylation of an unactivated alkene using synthetic gas (1 1 H2-CO) and a Rh(I) catalyst (Scheme 8).22 The reaction was typically performed at 40°C in toluene at a pressure of 75 atm. Conversions of 99% were obtained following careful reaction optimization. Variation in the concentration of catalyst could be used to alter the regioselectivity of the reaction. 

In conclusion, progress has been made towards the development of a general and robust solid-phase synthesis of PMRI-peptides. Nevertheless, the published data suggest that additional investigations should be performed to further optimize this synthetic approach. 

Various techniques have been developed that enable the rapid preparation and screening of large numbers of different compounds by parallel solid-phase synthesis. Reactions can, for instance, be conducted in an array of reactors such as that sketched in Figure 1.1. Synthesizers with up to approximately 600 discrete reactors are commercially available these enable the automated preparation of compound libraries containing up to 0.1 mmol of each compound. Discrete reactors are also well suited for the development and optimization of solid-phase chemistry. 

The acylation of amines on insoluble supports is one of the most thoroughly investigated reactions in solid-phase synthesis. The continuous optimization of peptide bond formation in recent decades has led to protocols that enable racemization-free, quantitative acylations of support-bound peptides with protected amino acids. In recent years, the range of amides available by solid-phase synthesis has expanded significantly to include, for example, N-alkylated peptides and anilides. New strategies for the preparation of amides, such as C-carbamoylations and the Ugi reaction, have also been successfully realized on insoluble supports. 

A microwave-assisted solid-phase synthesis of the antimicrobial oxazo-lidinone pharmacophore is described herein as a demonstration of the utility of this emerging technology toward drug discovery.4 The optimization process and full experimental details for the synthesis of a small library of oxazolidinones are exemplified. 

For solid-phase synthesis various linker molecules were constructed on the ULTRA resin 15. To determine the optimal spacer length, ULTRA resins were coupled with spacers of variable length. With 4-(4 -acetoxy-methyl-3 -methoxy-phenoxy) butyrate and a loading of 2.5 mmol/g the synthesis of heterocycles and peptides was investigated. A pyrazole carboxylic acid was prepared using a procedure established for Wang polystyrene... 

In solid-phase synthesis intermediates and products are bound to a solid support via a covalent linker. The linker must allow selective removal of the final product from the support, but must be stable under the reaction conditions throughout the synthesis. The advantage of a solid-phase approach is that reagents can be used in large excess to drive reactions to completion and most side products are just washed off from the solid support. However, the solid-phase implies steric constraints onto the reactions performed. The choice of method depends on the synthetic problem it is often not obvious and usually results from a reaction optimization study. 

Each synthetic step of syntheses performed on insoluble supports must generally be optimized to such an extent to yield intermediates of high purity, because these polymer-bound intermediates cannot be purified. Once such an optimized solid-phase synthesis has been developed, final products of high purity can often be obtained directly after cleavage from the insoluble support and evaporation of the cleavage reagent (e.g., trifluoroacetic acid). 

In one example sequence the technology has been used to synthesize a variety of amides from amines and acid anhydrides. It is currently also being used to optimize reactions through the variations of auxiliaries and solvents and might become an interesting and more direct alternative to solid-phase synthesis. 

The main goal of this chapter is to describe the synthesis details of complex, orthogonally protected peptide constructs. Thus, major emphasis is placed on the peptide chain assembly design and practice and the alterations from the solid-phase synthesis of simple, nonmodified peptides. The technology for peptide purification and quality control is not significantly different from that of other peptides, and these methods will be just briefly described. Many chapters of this book focus on the optimization of HPLC and MALDI-MS procedures for peptide separation and analysis and illustrate the expected and/or acceptable quality control parameters. 

Support-bound sulfonylhydrazones have been reduced to alkanes by sodium borohydride (Entry 5, Table 3). This reaction, which has not yet been fully optimized for solid-phase synthesis, should enable the support-aided conversion of ketones into alkanes under mild reaction conditions. 

Recent literature contains a multitude of examples of synthetic organic methodologies which have been optimized and applied to the solid-phase synthesis of combinatorial libraries [2]. In fact, the production of a number of these libraries has been realized on such systems as the Multipin SPOC [8], the DIVERSOMER [9] and the OntoBLOCK [10], All three apparatuses allow the automated production of spatially dispersed combinatorial libraries and facilitate the isolation, identification, screening and archiving of single compounds in distinct physical locations which are crucial factors during lead discovery and optimization. 

---