Natural product libraries synthesis

Only recently the progress in solid-phase synthesis has met the demands of the intrinsic complexity of natural product library synthesis on solid support [10]. The aim of this chapter is to describe the different approaches followed in this science and to highlight these with notable examples demonstrating the current state of the art. 

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. 

Another example in which literature results were reanalyzed in view of the PSSC concept concerns the development of ligands for the farnesoid X receptor. The farnesoid X receptor is a transcriptional sensor for bile acids, the primary products of cholesterol metabolism, and plays an important role in lipid homeostasis. The farnesoid X receptor was, until recently, an orphan receptor, which means that no specific ligands existed for this receptor. Selective ligands for this receptor have been found in natural product libraries described by Nicolaou et al. The group of Nicolaou developed solid phase synthesis methods to make combinatorial libraries based on a benzopyran core structure. " A 10,000-membered combinatorial library based on the benzopyran core structure was synthesized and screened for activity on the farnesoid X receptor. The first specific ligands for the... 

While in the recent past it was extremely difficult, time consuming and labour intensive to build such a library from purified natural products, with the advent of newer and improved technologies related to separation, isolation and identification of natural products the situation has improved remarkably. Now, it is possible to build a high quality and chemically diverse natural product library that can be suitable for any modern HTS programmes. Natural product libraries can also be of crude extracts, chromatographic fractions or semi-purified compounds. However, the best result can be obtained from a fully identified pure natural product library as it provides scientists with the opportunity to handle the lead rapidly for further developmental work, e.g. total or partial synthesis, dealing with formulation factors, in vivo assays and clinical trials. 

For a recent and comprehensive review of solution-phase and solid-phase synthesis of natural product libraries, see a) D. G. Hall, S. Manku, F. Wang,/. Comb. Chem. 2001, 3, 125-150 b) L. Wess-[ohann, Curr. Opin. Chem. Biol 2000, 4, 303-309 c) L. J. Wilson in Solid-Phase Organic Synthesis , K. Burgess (Ed.), Wiley-Interscience New York, 2000 d) C. Watson, Angew. Chem. Int. Ed. 1999, 38, 1903-1908. 

A specific class of libraries in which biologically active natural products are either built during the synthesis or used as scaffolds to be decorated has recently emerged and has gained considerable attention for pharmaceutical purposes. The biological information contained in the natural scaffold increases the chances of discovering novel active structures. Some examples depicted in Figs. 4.14-4.18 demonstrate the potential of natural product libraries. 

Merging chemical synthesis and biosynthesis as a strategy of the total synthesis of natural products and natural product libraries 12AG(E)4012. Palladium-mediated total synthesis ofbioactive natural products 13S1271. Recent contributions from the asymmetric aza-Michael reaction to alkaloids total synthesis 13NPR1211. 

Solid-Phase Organic Synthesis of Natural Products Libraries. 216... 

P. A. Keifer 1998, (New methods for obtaining high resolution NMR spectra of solid-phase-synthesis resins, natural products, and solution-state combinatorial chemistry libraries), Drugs Future 23, 301-307. 

The term biology-oriented synthesis (BIOS) [45] has been used to describe the design of compound libraries based on biologically relevant chemical space [46]. The areas in protein structures that participate in productive protein-ligand interactions have been, for the most part, already defined by natural products and drugs. Thus libraries inspired by natural products and other bioactive molecules are expected to have a higher probability of biologically activity than randomly synthesized molecules [47,48]. 

More recently, Somfai and coworkers have reported on the efficient coupling of a set of carboxylic acids suitable as potential scaffolds for peptide synthesis to a polymer-bound hydrazide linker [24]. Indole-like scaffolds were selected for this small library synthesis as these structures are found in numerous natural products showing interesting activities. The best results were obtained using 2-(7-aza-l H-benzo-triazol-l-yl)-l,l,3,3-tetramethyluronium hexafluoride (HATU) and N,N-diisopropyl-ethylamine (DIEA) in N,N-dimethylformamide as a solvent. Heating the reaction mixtures at 180 °C for 10 min furnished the desired products in high yields (Scheme 7.4). In this application, no Fmoc protection of the indole nitrogen is required. 

Ley S V, Baxendale IR, Myers RM (2006) The use of polymer supported reagents and scavengers in the synthesis of natural products. In Boldi AM (ed) Combinatorial synthesis of natural product-based libraries. CRC Press Boca-Raton, pp 131-163... 

Combinatorial Synthesis of Natural Product-Based Libraries... 

The requirement for diverse compound libraries by means of solid-phase synthesis led to the development of hnkers for most functional groups found in organic synthesis. The number of hnkers developed for a specific group also reflects the distribution of pharmacophoric groups present in natural products and other bioactive compounds. Tab. 3.16 gives an overview of examples of hnkers for different functional groups. 

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