انجمن شیمیدانان جوان

Polymer Supported Reactions

Organic Synthesis on Polymer Beads

The breakthough work of R. Bruce Merrifield demonstrated that specific polypeptides (i.e., with a defined length and sequence) could be synthesized by a repetitive series of reactions on insoluble polymer beads. This discovery was not only essential for the advancement for protein science, but, as it turned out, had a tremendous impact on other areas of bio-organic chemistry.

Performing organic reactions on beads presents many advantages: The product at each step remains chemically bound to the bead. Excess reagent can be used, then conveniently washed away when the beads are filtered. The whole process can be automated, so that a simple reactor connected to a collection of pumps and reagent reservoirs can be computer controlled to make even complicated molecules. The main drawbacks are that each step of the synthesis must be very efficient, because by-products bound to the beads cannot be removed, and will possibly contaminate the final product. Also, the loading capacity of the beads is limited, so only small amounts of products can be made. In addition, recent work in combinatorial chemistry has demonstrated that even well-studied organic reactions occasionally behave in unexpected ways on polymeric beads compared to conventional solutions.

Polypeptide Synthesis

The synthesis of polypeptides on polymeric supports has been worked out very thoroughly. Better than 99% efficiency in each step is now routine, leading to quite pure products. The automated systems are very convenient. One simply tells the computer what sequence of amino acids to use, loads the required reagents into the system, and then goes away while the computer performs the synthesis. When the chemist returns, the computer presents him or her with a solution of the "designer" polypeptide, ready for isolation and use.

In its best known form, the chemistry begins with the synthesis of poly(chloromethylstyrene) beads crosslinked with divinyl benzene via suspension polymerization. These particular beads have become known as "Merrifiield resin," and are available commercially.

Of course, the relative amount of crosslinker can be varied to alter the properties of the bead. (For simplicity, the crosslinking repeat unit will be omitted from later drawings.)

The chloride can be displaced with the carboxylate anion of an amino acid, while its amino group is blocked by a protecting group. (A wide variety of protecting groups are available for this purpose.) This reaction places the first amino acid on the bead. Excess unattached amino acid is washed away from the bead.

The protecting group is then removed by washing the beads with the appropriate reagent.

A second N-protected amino acid is then coupled on using a condensation reagent such as DCC.

This places a second amino acid on the beads, and, once again, the nitrogen atom can be deprotected as before in preparation for yet another condensation with a third amino acid. Etc. etc. etc.

Eventually, a specific polypeptide is formed bound to the bead. In a final step, a unique reagent is used to cleave the final product from the bead.

Combinatorial Chemistry

Obviously, polypeptides are of interest to biochemists, but the principles described above are applicable to any series of organic reaction. This technique has been generalized to polynucleotides, polysaccharides, and also recently a wide variety of general organic reactions. There are even commercial machines for synthesizing designer peptides, oligonucleotides, and other molecules automatically via chemistry on beads. In the 1990's, with the advent of computer controlled multi-reactors and micro-scale biological automated bioassays, medicinal chemists have taken to polymer supported organic reactions in a huge way.

Specialized systems now in use are capable of synthesizing thousands of different related compounds simultaneously for pharmaceutical testing. This new technology is made possible by the same advantages mentioned above for polypeptide synthesis. The intermediates and products are bound to insoluble beads that can be collected by filtration, and excess reagents easily washed away.