Natural products combinatorial synthesis,

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. 

The feasibility of multi-step natural product total synthesis via solid-phase methodology, and its application to combinatorial chemistry, was first achieved by Nicolaou and co-workers in epothilone synthesis and in the synthesis... 

The prostaglandin family constitutes one of the most pharmacologically active low molecular-weight natural products. Combinatorial access to prostaglandins is based on two main strategies of synthesis of its E- and F-series developed by Janda and Chen ° ° and F.llman et al. ° In the... 

The Pictet-Spengler reaction has mainly been investigated as a potential source of polycyclic heterocycles for combinatorial apphcations or in natural product synthesis [149]. Tryptophan or differently substituted tryptamines are the preferred substrates in a cyclocondensation that involves also aldehydes or activated ketones in the presence of an acid catalyst. Several versions of microwave-assisted Pictet-Spengler reactions have been reported in the hter-ature. Microwave irradiation allowed the use of mild Lewis acid catalysts such as Sc(OTf)3 in the reaction of tryptophan methyl esters 234 with different substituted aldehydes (aliphatic or aromatic) [150]. Under these conditions the reaction was carried out in a one-pot process without initial formation of the imine (Scheme 86). 

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. 

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],... 

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... 

Abstract In this chapter different types of domino-processes are described which consist of the combination of cationic, anionic, radical, pericyclic and transition metal-catalyzed as well other reactions. The methodology is used for the highly effective synthesis of carbocycles and heterocycles as well as of natural products and other interesting materials. It is also employed as an efficient tool in combinatorial chemistry. 

Combinatorial Derivatization for Immobilized Natural Product Skeletons and Combinatorial Semi-synthesis... 

Scheme 3.30 Derivatives of natural product skeletons and combinatorial semi-synthesis products.

In recent years, developments in high-throughput screening inspired many pharmaceutical companies to focus and rely on combinatorial chemistry, especially massive parallel synthesis, to find new lead structures. The employed chemistry is often simple and the concept depends on sheer numbers for success. The main research areas were heterocyclic and peptide chemistry, and the resulting structures often lacked complexity and diversity, and most importantly the chance to utilize the evolutionary advantage of natural products with their privileged structures. 

The term diversity-oriented synthesis (DOS) is relatively new and, as mentioned above, is usually defined as the synthesis of complex, natural product-like molecules using a combinatorial approach and employing the full palette of modern organic reactions. It may be a subject of discussion what exactly qualifies a molecule as being natural product-like [4], and in most cases the similarity to an actual natural product seems reciprocal to the number of synthesized compounds. However, even in less complex cases, the products may be highly substituted polycyclic structures with defined stereochemistry, reminiscent of natural products [19, 20]. In these cases, a moderately complex backbone structure is subsequently modified with a well-established set of selective reactions to introduce diversity. 

Other examples of Ugi reactions combined with RCM have been described in the literature. Hebach and Kazmaier reported the synthesis of conformationally fixed cyclic peptides [70] and Beck and Domling synthesized biaryl-containing natural product-like macrocycles using this method [41]. The same group also reported combination of Passerini and Horner-Wadsworth-Emmons reactions to obtain butenolides [67] and another variation for the combinatorial synthesis of thiazoles [69]. 

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