Planning from the Starting Material

Inter-monomer bonds are the easiest to break in such destructive reactions as chemical or enzymatic hydrolysis. As easily as these bonds are broken, they can be formed by common functional group transformations from readily available monomeric units. In these cases, retrosynthetic analysis of the target 

The cationic polymerization of monomer 25 occurs via the initial coordination the electrophilic initiator, PF5, at the indicated ring oxygen atom to produce the oxonium ion 26. The latter is attacked by another molecule of 25 at its electrophilic site, C-1, to form a new oxonium ion 27. Repetition of this process leads to the consecutive formation of a set of glycosidic bonds in a stereospecific fashion as defined by inversion of configuration in every single attack at C-1. It is clear that the nature of the reaction and the structure of the monomer ensures both the desired stereo- and regiospecificity. Debenzylation of the final polymer 28 readily affords the target product 23. 

This two-step cycle can be repeated, in principle, as many times as desired to form the polypeptide chain of the required length. At the end, only a final workup with acid (usually by a treatment with a strong anhydrous acid such as HF) is required to cleave the initial benzyl ester bond to the resin and liberate the free polypeptide. 

The utilization of the solid support cannot by itself simplify the problem of separating the (n) polypeptide from the mixture of its immediate precursor, the (n — 1) product, as both are bound to the resin. However, in this approach it is possible to use an excess of any reagent necessary to secure 100% conversion of the (n — 1) precursor as this excess can easily be removed from the resin-bound target product. 

The same principles found an even more spectacular application in the area of polynucleotide synthesis. Most importantly, it was recognized that the use of various types of solid support offered a number of promising strategic opportunities in other areas of organic synthesis. Thus the successful solution of what appeared to be initially a purely technical problem, of limited significance, led ultimately to results of enormous scientific importance. 

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