Complexing, small molecule

Taxol is the trademark name given to the complex small molecule, pachtaxel (Figure 7.1). The molecular complexity of paclitaxel is evident in the tetracyclic nucleus and 11 chiral centers. Throughout this text, I will use the brand name Taxol synonymously with its generic name, paclitaxel. 

Molecular Complexes. These species are formed by noncovalent interactions between the substrate and ligand. Among the kinds of complexspecies included in this class are small molecule-small molecule complexes, small molecule-macromolecule species, ion-pairs, dimers and other self-associated species, and inclusion complexes in which one ofthe molecules, the host, forms or possesses a cavity into which it can admit a guest molecule. 

It is critical to this chemical genetic approach to have a library of compounds that have a high probability of being relatively selective otherwise, the ability to interpret the results becomes at least as complex as deciphering highly poly-genetic phenotypes. To address this, diversity-oriented synthesis has been proposed to provide arrays of complex small molecules that are easily synthesized. The natural-product basis for many of the molecules and their complexity are believed to contribute to their cellular potency and selectivity (6). This chemical genetic approach has been applied to identify novel inhibitors of alpha-tubulin and histone deactylation (7). 

Fig. 33 Complexing small-molecule additive and polymer guests in CD-star polymers. The hypothetical graph in the bottom right corner suggests the relative energy states that may be experienced by polymer B along the dashed line in the reference schematic, where (a) refers to the A-B energy state, (b) to the B-B energy state, and (c) is the B-CD energy...

Life is easier with two stairways, marked clearly up and down . It has become clear within the last five or six years that the cell does the same. Let us look at some typical examples of up staircases, for the synthesis of glycogen, fats, and some of the more complex small molecules the cell uses. We will leave the most complex of the up staircases, those for protein and nucleic acid synthesis, to a chapter of their own. 

More complex small molecules can also be made by metathesis cascades and tandem reaction sequences involving olehn metathesis components [41], The examples illustrated in Fig. 4.13 include inter- and intramolecular enyne metathesis between an olefin and an alkyne [42], ring-opening cross metathesis to form new substituted acyclic olefins [43], ring-opening ring-closing sequences... 

The developed solid-supported, chemoselective Pauson-Khand reaction has been subsequently applied toward the preparation of complex tricyclic scaffolds for diversity-oriented synthesis." The triple bond was introduced into the substrate via a stereoselective Ferrier reaction generating the ene-yne 86, followed by immobilization on the solid support. The subsequent Pauson-Khand reaction yielded the desired tricyclic product 87 in an efficient fashion (however, no yields were provided), which was further elaborated toward structurally complex small molecule libraries (Scheme 6.20). 

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