Reagent-Based Strategies

The authors found that by varying the level of steric hindrance associated with the dienophiles, they were able to modify the outcome of the potential double Diels-Alder reaction. When disubstituted dienophiles such as maleimides were used, the double Diels-Alder reaction occurred smoothly to yield a tetracyclic skeleton (4). If tri- or tetrasubstimted dienophiles were used, only one Diels-Alder reaction occurred to give a bicyclic diene-containing skeleton (5) that could either be treated as a discrete product or reacted further with a more reactive dienophile to again give a tetracyclic structure (6). 

By combinatorial variation of the dienophiles and polymer-bound aldehydes used, the synthesis of 29,400 compounds was possible, broken down into 800 bicyclic dienes and 28,600 potential tetracycles. Further skeletal variation was achieved using different heterocyclic dienophiles for some examples. This work effectively illustrates the scale of 

Work by Taylor et al. from 2004 neatly illustrates another potential advantage of solid-phase synthesis this work was based on the generation of reactive dihydroisoquinoline and dihydropyridine intermediates to be used in further reactions. These species are known to be unstable when stored for any period of time, even under seemingly inert conditions however, once attached to a solid support, they proved immune to degradation even after storage for 30 days at room temperature. 

This methodology produced 12 distinct molecular skeletons, aU of which possessed a pendant hydroxyl group resulting from cleavage of the solid support, which allowed the use of microarray technology for protein binding assays. 

---

In the previous chapter we discussed various reagent-based strategies for the enantioselective formation of chiral centres. The next two chapters are also concerned with reagent-directed strategy but with an important difference. The source of asymmetry is used in a much lower concentration it is a catalyst. We may put in a few milligrams of an optically active compound and get out grams or even kilograms of enantiomerically pure product. This chapter concerns the formation of C-O and C-N bonds, the next the formation of C-H and C-C bonds. 

Jamois EA, Hassan M, Waldman M. Evaluation of reagent-based strategies in the design of combinatorial library subsets. J Chem Inf Comput Sci 2000 40 63-70. 

In general, reagent-based selection is much faster and more convenient to execute in the laboratory as compared with the product-based selection. On the other hand, the latter strategy usually provides more accurate results. There exists a potential to combine both approaches to achieve more optimal results, particularly in the case of large exploratory virtual combinatorial libraries, for which mass random synthesis and screening are not economically feasible. In this article, we demonstrated the usefulness of property-based approach for selection of optimal GPCR ligands. 

Itsuno etal. developed another borohydride-based strategy using amino acid derived reagents such as 11 in 1981. They can be obtained by treating the corresponding aminoalcohol such as 10 with BH3 in THF, and are applied in ketone reductions in a 1.25-fold excess together with 2.5 equivalents of BHs. ... 

---