Combinatorial Chemistry Review

Combinatorial Synthesis on Solid-Phase

Since Merrifield pioneered solid phase synthesis back in 1963, work, which earns him a Nobel Prize, the subject, has changed radically. Merrifield’s Solid Phase synthesis concept, first developed for biopolymer, has spread in every field where organic synthesis is involved. Many laboratories and companies focused on the development of technologies and chemistry suitable to SPS. This resulted in the spectacular outburst of combinatorial chemistry, which profoundly changed the approach for new drugs, new catalyst or new natural discovery.

The use of solid support for organic synthesis relies on three interconnected requirements:

Combinatorial Synthesis on Solid Phase

1) A cross linked, insoluble polymeric material that is inert to the condition of synthesis;
2) Some means of linking the substrate to this solid phase that permits selective cleavage of some or all of the product from the solid support during synthesis for analysis of the extent of reaction(s), and ultimately to give the final product of interest;
3) A chemical protection strategy to allow selective protection and deprotection of reactive groups.

Merrifield developed a series of chemical reactions that can be used to synthesise proteins. The direction of synthesis is opposite to that used in the cell. The intended carboxy terminal amino acid is anchored to a solid support. Then, the next amino acid is coupled to the first one. In order to prevent further chain growth at this point, the amino acid, which is added, has its amino group blocked. After the coupling step, the block is removed from the primary amino group and the coupling reaction is repeated with the next amino acid. The process continues until the peptide or protein is completed. Then, the molecule is cleaved from the solid support and any groups protecting amino acid side chains are removed. Finally, the peptide or protein is purified to remove partial products and products containing errors.

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