Solid phase multistep

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. 

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]. 

Although the chemistry of the liquid-phase MCR libraries was introduced in the early 1960s, their profound preparative advantages were realized only recently. The solid-phase peptide libraries have been used since 1982, with various other solid-phase multistep libraries being produced subsequently. 

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. 

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. 

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... 

Removal of Side Products Using solid-phase protocols, unreacted reagents, consumed reagents, and the products of protecting group manipulations are washed away. Solution-phase strategies will be limited to a single transformation per step with subsequent purification of the product (a multistep route) unless the byproducts either (1) are not produced or (2) do not interfere with subsequent transformations. 

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. 

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. 

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). 

The resin-bound perfluoroalkylsulfonyl linker is compatible with many common solid-phase reactions, such as tin dichloride-mediated aromatic nitro group reduction, trifluoroacetic acid-mediated tBoc deprotection, reductive amination reactions, acylation, and sulfonation. It is possible to perform several sequential synthetic reactions on the nonflate resin so that multistep syntheses can be carried out. The solid-phase approach provides an operationally simple, inexpensive, and general protocol for the cleavage... 

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 difficulty of designing a sequence of compatible reactions, refining the experimental conditions and reaching near-quantitative yields over multistep procedures, is reflected in the proportionally modest number of mature chemical diversity systems, compared to the abundant number of organic reactions described on solid phase. 

Combinatorial chemistry can be carried out in solution or on solid support. Most solution combinatorial chemistries are typically limited to one-step reactions, whereas solid-phase chemistries often involve multistep processes that include resin manipulation, washing, drying, cleavage of the products from the resin, etc. 

The synthesizer can produce as many as 200 compounds a week through single-step automated reactions that require minor cleanup routines or about 60 compounds a week through multistep reaction sequences that include labor-intensive liquid liquid extractions or solid-phase cleanup. 

Using solid-phase chemistry, with the reactant attached to a support, and multistep syntheses, in which appropriate reagents are passed over the reactant on the support to prepare single or multiple products that are cleaved from the support and split and mixed so that subsequent steps have multiple starting materials... 

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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