Demon, arithmetic

By the time j ou get to a ten step synthesis, the arithmetic demon ensures that the yield is down to a miserly 35%. And this with 90% yield in eaeh step So clearly a short synthesis is a good one. But we ean cheat the arithmetic demon by making our five steps convergent rather than linear. The convergent version is this ... 

The preparation of peptides and nucleotides involves the iterative repetition of three simple steps monomer activation, coupling to the growing chain, and deprotection to unmask a new reactive terminus. The arithmetical demon of linear syntheses, whereby the overall yield decreases exponentially with any loss in yield for each cycle, had forced chemists to perfect these reactions to the point of being practically quantitative. The availability of such robust protocols was a necessary prerequisite for combinatorial chemistry. Outside the peptide and nucleotide areas, synthesis of a library is often far less time consuming than the development of optimized reaction conditions. 

Assembling a target composed of 65 building blocks (n = 64) looks less than appealing if attempted via a linear route, as this route is virtually blocked by the arithmetic demon . At the same time, though, the task does not look prohibitively complicated if a convergent route for its synthesis is feasible. 

The experiment requires 7.5 grams of drug, which requires a substantial synthetic effort if the arithmetic demon besets the work, as usually it does. An unoptimized six-stage synthesis might proceed in 50% yield per step. Making... 

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