Natural product libraries methodology

Abstract In the continuous drive to increase screening throughput and reduce sample requirement, microarray-based technologies have risen to the occasion. In the past 7 years, a number of new methodologies have been developed for preparing small molecule microarrays from combinatorial and natural product libraries with the goal of identifying new interactions or enzymatic activities. Recent advances and applications of small molecule microarrays are reviewed. 

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. 

Straightforward, versatile, and generates libraries of macrocyclic pseudo peptides with unprecedent functional and skeletal diversity. For example, natural product-inspired biaryl ether-cyclopeptoid macrocycles were obtained by this methodology [98, 99]. 

Access to libraries of complex and diverse small mol- synthesis in addition to the development of newer and ecules demands advancements in synthetic methodologies, sophisticated reactions for this purpose. Natural product... 

One of the earliest researchers in the area of natural product-like libraries is K.C. Nicolaou. Inspired by the total synthetic efforts of his group on many important natural product targets and coupled with his interest in synthetic methodology and chemical biology, Nicolaou reported a number of elegant examples (see Chapter 11) that include natural product-like libraries based upon Taxol, " sarcodictyins, epothiolones, vancomycin, muscone, and psammaplin a. ... 

Diverse polyketide-type libraries were synthesized using a-chiral aldehydes attached by a silyl linker to a hydromethylpolysyrene resin (Figure 11.24). " Aldol chain extension with chiral ketone modules, and subsequent ketone reduction and manipulation on the solid support led to elaborated stereopentad sequences found in natural products such as 6-deoxyerythronolide B and discoder-molide. Based on the biosynthesis of erythromycin, the same methodology was used in the combinatorial synthesis of polyketide sequence mimetics with a great variety of chain-extending units. " ... 

A constant interest in the development of new rapid methodologies for the preparation of oxazole libraries is motivated by their presence in numerous biologically active natural products. Janda and coworkers were first to show that oxazoles can be obtained by microwave-assisted treatment of polymer-bound a-acylamino-j8-ketoesters with Burgess reagent [68]. Hydroxybutyl-functionalized /anda/el resin was used for this investigation, with key steps being monitored by on-bead FT-IR. First, a resin-boimd acetoacetate was pre-... 

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