Solid phase synthesis SPOS

One of the cornerstones of combinatorial synthesis has been the development of solid-phase organic synthesis (SPOS) based on the original Merrifield method for peptide preparation [19]. Because transformations on insoluble polymer supports should enable chemical reactions to be driven to completion and enable simple product purification by filtration, combinatorial chemistry has been primarily performed by SPOS [19-23], Nonetheless, solid-phase synthesis has several shortcomings, because of the nature of heterogeneous reaction conditions. Nonlinear kinetic behavior, slow reaction, solvation problems, and degradation of the polymer support, because of the long reactions, are some of the problems typically experienced in SPOS. It is, therefore, not surprising that the first applications of microwave-assisted solid-phase synthesis were reported as early 1992 [24],... 

The initial report on solid-phase synthesis appeared in 1963, when Merrifield [1] developed a way to make peptides by solid-phase synthesis. Since then the general field of solid-phase organic synthesis (SPOS) has grown enormously. The fundamental technique is based on polymeric resin beads to which a reactant is covalently bonded (Fig. 2.3-1). 

Related quinazoline alkaloids have also been prepared using SPOS. For example, in 2001, Wang and Sim reported on the solid-phase synthesis of verrucine A 18 and its... 

At the time of writing this book, SPOS is in an area of reladve infancy but has considerable potential. One of the main difficulties in SPOS lies in the lack of techniques available to monitor reacdons carried out on polymer supports. Unlike reacdons in solution phase, reactions on solid support cannot be monitored with relative ease and this has hindered the progress as well as the efficacy of solid supported synthesis of small non-peptidic molecules. Despite these difficulties, a large body of studies is available for SPOS. Recent reviews incorporate... 

In the 1990s the technique of solid-phase organic synthesis (SPOS) became generally popular, but especially in the medicinal chemistry community, for lead detection and lead optimization via combinatorial techniques. The combination with microwave irradiation brought an elegant solution for the problem of the notoriously slower reactions compared to those in solution phase. 

Since 1986, when the very first reports on the use of microwave heating to chemical transformations appeared [147,148], microwave-assisted synthesis has been shown to accelerate most solution-phase chemical reactions [24-27,32,35]. The first application of microwave irradiation for the acceleration of reaction rate of a substrate attached to a solid support (SPPS) was performed in 1992 [36]. Despite the promising results, microwave-assisted soHd-phase synthesis was not pursued following its initial appearance, most probably as a result of the lack of suitable instriunentation. Reproducing reaction conditions was nearly impossible because of the differences between domestic microwave ovens and the difficulties associated with temperature measurement. The technique became a Sleeping Beauty interest awoke almost a decade later with the publication of several microwave-assisted SPOS protocols [37,38,73,139,144]. There has been an extensive... 

A simple predecessor of the CEM setup for microwave-mediated SPOS was employed by Murray and Gellman in their synthesis of 14-hehcal 6-peptides [42], A 4 mL polypropylene solid-phase extraction tube was inserted into a 10 mL CEM vessel, allowing for both microwave heating and simple resin manipulation (Eig. 11). While using this setup gave reproducible results for their experiments, a discrepancy between the reactions target (set) temperatures and the actual temperatures was observed. Therefore, use... 

---