Solid-phase organic synthesis natural products

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],... 

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. 

Solid-phase organic synthesis has emerged as a powerful tool for the synthesis of chemical hbraries. A major drawback to sohd-phase chemistry is that it is difficult to directly monitor the desired chemical reaction on resin. Standard analytical techniques for reaction optimization are available after the reaction product is cleaved from the solid support. However, the typically harsh conditions necessary to remove the reaction product from the solid support may introduce impurities and undesired side products, thus masking the true nature of the reaction being monitored. Both IR and spectroscopy have been used to monitor the progress of reactions on the solid phase. This chapter reviews the use of NMR spectroscopy as a tool to monitor solid-phase reactions directly, without having to cleave the product from the resin prior to analysis. 

Wilson, L.J., Recent advances in solid-phase synthesis of natural products, in Solid-Phase Organic Synthesis, Burgess, K., Ed., John Wiley Sons, New York, 2000, chap. 8. 

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

SOLID-PHASE ORGANIC SYNTHESIS OF DRUGS AND NATURAL PRODUCTS... 

Eifler-Lima VL, Graehin CS, Uchoa FDT, Duarte PD, Correa AG. Highlights in the solid-phase organic synthesis of natural products and analogues. J. Braz. Chem. Soc. 2010 21 1401-1423. 

The functional group tolerance of the ruthenium-based metathesis catalysts has had a tremendous impact on solid-phase organic synthesis. The efficacy of the reaction in solution generally translates directly to solid-phase transformation and its potential has been harnessed in a number of library syntheses, solid-phase syntheses of natural products, or diversity-oriented syntheses. It enables the use of chemically robust alkenes as linkers which can be cleaved by RCM or CM. It, of course, provides new manifolds of diversification in diversity-oriented synthesis as has been elegantly shown in landmark examples by Schreiber and Nelson. Another metathesis application of paramount importance is in peptide chemistry where solid-phase synthesis is omnipresent. The ability to stabilize secondary structures in short peptide motifs and replace pharmacologically unsuitable disulfide bonds or simply restrict the conformation of a peptidic library has already been successfully implemented in a number of important examples. The orthogonality of the metathesis reaction to peptide chemistry provides a really powerful tool in this regard. 

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