Natural products solid phase syntheses

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. 

Sequential pyrrolidine and hydantoin ring-forming reactions via intramolecular [2+3] cycloaddition have been applied to the stereoselective solid-phase synthesis of conformationally constrained tricyclic triazacyclopenta [C]pentalene scaffold 43 < 1999JOC8342>. These novel compounds 43 share the structural complexity characteristic of certain alkaloid natural products, angular triquinanes. The retrosynthetic analysis is shown in Scheme 87. 

One of the key steps in combinatorial solid-phase synthesis is clearly the cleavage of the desired product from the solid support. A variety of cleavage protocols have been investigated, depending on the nature of the linker employed. A complete micro-wave-assisted protocol, involving attachment of the starting material to the solid support, scaffold preparation, scaffold decoration, and cleavage of the resin-bound product, would seem desirable. 

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],... 

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. 

As six-membered heterocycles are present in a number of natural products and biologically important molecules, solid-phase synthesis of these has been reported very often (Fig. 3.9). Solid-phase synthesis for nearly every six-membered ring including one nitrogen atom are known piperidines (272) [376], tetrahydropyridines (273) [377, 378], dihydropyridines (274) [219, 379, 380], pyridines (275) [349, 381-386], (Scheme 3.37), piperidinones (276) [387], dihydropyridones (277-279) [313, 378, 388-390], pyridinones (280-281) [328, 329] and piperidindiones (282) [391] derivatives. In contrast, the synthesis of six-membered rings with one single oxygen is rarely described. Nevertheless, solid-phase synthesis of dihydropyrans (283-284) [392-394] and tetrahydropyrans (285) [335, 336] has been reported. 

The recently described solid phase synthesis of 6,6 -spiroketals provides an example in which natural product analogs were completely assembled on the solid phase. The authors described solid-phase synthesis procedures to synthesize 6,6 -spiroketals, which are structural motifs found in many... 

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... 

The antibiotic viscosin from Pseudomonas viscosa (Scheme 8) is a cyclo-depsipeptide acyl-ated at the N-terminus with D-3-hydroxydecanoic add.[103 112] The C-terminal carboxy group is esterified with the hydroxy group of the Thr3 residue. The synthesis of this natural product presents the problem of an ester ring closure and was performed in two steps with initial solid-phase synthesis of the Thr3-0-branched linear intermediate followed by ring closure with formation of the amide bond.1 131... 

RECENT ADVANCES IN SOLID-PHASE SYNTHESIS OF NATURAL PRODUCTS... 

Cyclative Cleavage Strategies for the Solid-Phase Synthesis of Heterocycles and Natural Products... 

As a representative example, the rather complex natural-product dysidiolide was synthesized by methods amenable to combinatorial synthesis (30). Using a cycloaddition-based approach to the dysidiolide core, a solid-phase synthesis of epi-dysidiolide (Fig. 4) and analogs thereof was developed. 

Brohm, D., Metzger, S., Bhargava, A., Muller, O., Lieb, F., and Waldmann, H. (2002) Natural products are biologically validated starting points in structural space for compound library development solid phase synthesis of dysidiolide-derived phosphatase inhibitors. Angew. Chem. Int. Ed. 41, 307-311. 

Despite this proven record of biological significance there had been some doubts if natural products are suitable and accessible lead structures for combinatorial libraries by solid-phase synthesis. In contrast to the diversity-oriented approach of library design, which is driven by the underlying chemistry of reliable reactions with broad substrate scope [4], natural product... 

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. 

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