Solid-Phase Synthesis Small Organic Molecules

3 Solid-Phase Synthesis Small Organic Molecules 

All of the above-mentioned aspects will also be illustrated through the detailed description of a specific example (1), which spans every phase of a successful SPS and shows its potential to generate synthetic organic libraries (Section 3.4). The same will happen for several other recent examples (Section 3.5) using the analysis model built in Sections 3.1-3.3. 

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SOLID-PHASE SYNTHESIS SMALL ORGANIC MOLECULES... 

Solid phase synthesis of organic molecules is exemplified by the pioneering work of Bunin and Ellman on solid phase synthesis of a small benzodiazepine library (29). As shown in Fig. 1, a substituted benzophenone was tethered to a solid support via a substituent (Ri). The solid supported benzophenone was then elaborated through five synthetic steps to the target benzodiazepines with four points of diversity. Cleavage from the solid support re-... 

Solid-phase synthesis of biomolecules, of which peptides are the prime example, is well established. The search for more effective therapeutic agents creates a need for different strategies to synthesize peptides with C-terminal end groups other than the usual carboxylic acid and carboxamide functionalities. Methods described herein are readily generalized to small nitrogen-containing organic molecules. 

Nowadays, solid-phase synthesis has been used as a powerful tool in organic chemistry, especially to prepare small molecule libraries. New linkers to obtain different functionalities after cleavage have been developed. There are different linkers strategies (Fig. 3.2), for example traceless linkers, multifunctional linkers, safety catch linkers, fragmentation/ cycloreversion cleavage linkers, cyclization cleavage linkers, which are useful methods for combinatorial solid-phase chemistry. 

A key element in the original Merriheld procedure of solid-phase synthesis is the solid support system. That system consists of two parts a resin head and a. linker, an organic compound used to join the hrst amino acid to the resin head. The resin beads used by Merriheld are small spherical objects made of cross-linked polystyrene. This material consists primarily of the polymer polystyrene whose linear molecules are linked to each other at various positions by the addition of divinylhenzene (CH2 = CHCgH jCH =CH2). The hnal cross-linked material is relatively rigid, with enough hexihility to permit... 

The famous Ugi reaction, the one-pot condensation of a carboxylic acid, an amine, an aldehyde or ketone and an isocyanide to yield an a-acylaminoamide, have recently been used as an efficient method for the synthesis of diverse libraries of small organic molecules such as benzodiazepines, pyrroles, lactams and diketopiperazines2. Even though some solution-phase Ugi reactions proceed rapidly, such reactions on solid phase have been found to take between one and several days. In 1999, Hoel and Nielsen17 performed the first microwave assisted, solid phase Ugi four-component condensation (see Scheme 5.5). 

Conventional liquid phase synthesis suffers from the limitation that each product or intermediate has to be separated from the other components of the reaction mixture. An elegant answer to this problem is to use a solid phase synthesis (SPS) approach. In such an approach the compounds are synthesized on a solid support and simple washing steps replace the laborious work up and isolation procedures. At the end of the synthesis the product is released from the solid support. The SPS of oligomers of amino acids or nucleotides is well estabilished and task chemists are facing now is the development of SPS routes for small organic molecules. 

The first traceless linkers for arenes were silyl linkers. This linker type was used in the synthesis of a benzodiazepine library, a milestone in the solid-phase synthesis of small organic molecules (Scheme 6.1.9). Synthesis of the linker involves lithium-halogen exchange and, after chlorosilane attachment, coupling with an... 

Peptides are not the only potential drug candidates. In most cases, other kinds of small organic molecules are preferred, because of their reduced susceptibility to enzymatic degradation. The split-mix method is fully applicable in the synthesis of organic libraries. Both sequential type and cyclic libraries can easily be prepared if the reaction conditions for solid phase are well developed. It has to be emphasized, however, that the advantages of the split-mix method can be fully exploited only in the case of multi-step synthetic procedures. For realization of the one-pot procedures suggested by Ugi [10], for example, the parallel procedures are better-suited. 

Patek M, Drake B, Lebl M, Solid phase synthesis of small organic molecules based on thiazolidine scaffold, Tetrahedron Lett., 36 2227-2230, 1995. 

Positional scanning, or 1-D indexing, was reported as a deconvolutive technique by Houghten and coworkers [35] and subsequently applied extensively to solid-phase peptide library synthesis. An example of solid-phase small organic molecule 2-D indexed library synthesis and deconvolution was reported by Berk et al. [36]. Description of this strategy, called spatially arrayed mixture (SpAM), and a comparison with classical positional scanning, are shown in Figure 8.9. 

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