Solid phase multistep syntheses

Two decades later, Furka [24,86] introduced the production of solid-phase peptide libraries, forming these by extending Merrifield s procedure. Such peptide libraries were mainly used as an improved method of searching for new pharmaceutically applicable peptide derivatives. It was gradually realized, that such compounds have limited variability and that, in general, peptides are often at disadvantages when administered orally. Consequently, it was also realized that widely differing libraries of other types of chemical compounds can be formed by solid-phase multistep syntheses [87]. 

One of the key technologies used in combinatorial chemistry is solid-phase organic synthesis (SPOS) [2], originally developed by Merrifield in 1963 for the synthesis of peptides [3]. In SPOS, a molecule (scaffold) is attached to a solid support, for example a polymer resin (Fig. 7.1). In general, resins are insoluble base polymers with a linker molecule attached. Often, spacers are included to reduce steric hindrance by the bulk of the resin. Linkers, on the other hand, are functional moieties, which allow the attachment and cleavage of scaffolds under controlled conditions. Subsequent chemistry is then carried out on the molecule attached to the support until, at the end of the often multistep synthesis, the desired molecule is released from the support. 

Solution-phase syntheses employing linking reagents provide an alternative to solid-phase organic synthesis when poor conversions and incomplete reactions yield deletion intermediates upon release from resin. Applications are highlighted in various multistep syntheses covered at the end of this chapter. 

Merrifield introduced his solid-phase peptide synthesis (SPPS) methodology in 1963 t l this has since become the preferred method of peptide synthesis. Two decades later, Fur-kaP5,56] extended Merrifield s techniques to the synthesis of libraries of peptides used for the screening of new, desirable pharmaceutical products. Because peptides do not necessarily represent the ideal candidates for therapeutics, more recent attention has focused on other libraries of compounds that can be prepared by solid-phase multistep procedures. Among the approaches used for such purposes, the HO-3CR and the U-4CR, and their combination with other reactions, are finding increasing applications. 

Polymeric reagents and catalysts have evolved from the polymers used in ion exchange and in solid phase peptide synthesis. Most ion exchange resins are prepared by functionalization of cross-linked polystyrenes, and are used for water purification and as acidic and basic catalysts. Peptides are synthesized on similar polystyrene supports. Multistep modifications of polymers are used to produce non-commercial reagents and catalysts. However, peptide and nucleotide syntheses still provide the best-developed examples of polymeric reagents, and ion exchange resins are the most widely used polymer-supported catalysts. 

The feasibility of multistep natural product total synthesis via solid-phase methodology, and its application to combinatorial chemistry, was first demonstrated by Nicolaou and coworkers in epothilone synthesis and in the generation of an epothilone library [152]. The traceless release of TBS-protected epoC 361 by RCM of resin-bound precursor 360 (Scheme 69) is an early and most prominent example for the strategy outlined in Fig. 11a. 

Unlike OS, solid-phase methods will virtually always be invented for application in combinatorial organic synthesis. To meet these specific needs, SPOS procedures will focus not on multistep reactions leading to a desired final compound but rather on a single type of synthetic transformation accomplished on... 

Monitoring reaction progress throughout a multistep synthesis is a relatively difficult task.22 Typical methods used for solution-phase synthesis, including thin-layer chromatography (TLC), GC, and most types of mass spectrometry (MS), are less informative for solid-phase methods. However, Fourier transform infrared (FTIR) spectroscopy and nuclear magnetic resonance (NMR) are particularly useful in solid-phase strategies. 

A multistep solid phase synthesis of (3-lactams with imines of benzaldehyde coming out from commercially available fluorinated a-amino acids has been reported in 2003 [77]. Using the Merrifield resin-bound imine [78, 79] in dichlor-omethane, the cycloaddition was carried out between -78°C and rt by addition of benzyloxyacetyl chloride in the presence of triethylamine. The resin cleavage using sodium methylate resulted in the two cis p-lactam derivatives (Scheme 20). 

Protocols of peptide chemistry and, to some extent, biooligomer synthesis (e.g., nucleotides, saccharides) are valuable sources of information on this topic with regards to solid-phase synthesis peculiarities. Here we focus on a particular functional group transformation, which takes the role of depro-tecting a masked functionality, namely the nitro-to-amine reduction. This approach provides a versatile tool for planning multistep derivatizations of heterocycles, as exemplified in Fig. 15.45... 

For the fast identification of lead compounds for novel, small molecule enzyme inhibitors or other ligands for proteins, the screening of large and diverse arrays of compounds prepared on insoluble supports is one of the most efficient approaches.1-8 Parallel solid-phase synthesis has been found to be particularly well suited for the preparation of such arrays of diverse compounds since multistep synthetic sequences on insoluble supports can be conducted on fully automated synthesizers. 

Traceless linkers enable the solid-phase synthesis of products which were formerly only accessible by tedious, multistep solution-phase chemistry. Some of these linkers tolerate a broad range of reaction conditions, giving the chemist plenty of freedom in the design of new solid-phase synthetic sequences. Interestingly, polystyrene-bound selenium reagents can also mediate useful chemical transformations of substrates during their attachment to the support, and thereby function both as reagents and as linkers. 

The 6-epi diastereomer of dysidiolide (7, Scheme 14.3) and seven analogs of it were synthesized using a solid-phase approach. A notable feature of the multistep reaction sequence on solid phase is that a wide range of transformations with vastly differing requirements could be successfully developed. Key transformations of the synthesis include an asymmetric Diels-Alder reaction with the chiral dienophile... 

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