Skeletal diversity

Sello JK, Andreana PR, Lee D, Schreiher SL (2003) Stereochemical control of skeletal diversity. Org Lett 5 4125 127... 

Straightforward, versatile, and generates libraries of macrocyclic pseudo peptides with unprecedent functional and skeletal diversity. For example, natural product-inspired biaryl ether-cyclopeptoid macrocycles were obtained by this methodology [98, 99]. 

Chapter 11. Graphic analysis of the skeletal diversity and complexity... 

Taylor, S. J., Taylor, A. M., and Schreiber, S. L. (2004) Synthetic strategy toward skeletal diversity via solid-supported, otherwise unstable reactive intermediates. Angewandte Chemie 43, 1681-1685. 

Schreiber apphed (4a)-catalyzed RCM in the development of some of the facets of diversity-oriented synthesis toward the stereochemical control of macrocycle skeletal diversity. In this work, he showed that a chiral element such as an amino alcohol, even many bonds from the ring closnre, can influence the stereochemical outcome of RCM of otherwise identical complex substrates like a chiral auxiliary via diastereomeric transition states. Depending on which isomer is used, a completely different reaction pathway is observed. ... 

Burke MD, Berger EM, Schreiber SL. A synthesis strategy yielding skeletally diverse small molecules combinatorially. J. Am. Chem. Soc. 2004 126(43) 14095-14104. 

An important (and intellectnally challenging) goal in DOS is to develop efficient synthesis pathways that yield products with diverse displays of chemical information in three-dimensional space. To achieve this goal access to stereochemical and skeletal diversity is reqnired. 

Recently, Schreiber et al. have used macrolides and their linear precursors to probe the relative influences of stereochemical and skeletal diversity upon biological function. A library of 122 macrolides and their 122 linear precursors (Figure 9.5d) was evaluated in 40 different cell-based assays. Statistical analysis of the results revealed... 

There have been a number of advances in synthesis directed toward generating skeletal diversity in DOS. At present, different reagents are used to transform a common substrate with the potential for diverse reactivity into a collection of products having distinct molecular skeletons. These reagent-based skeletal diversity-generating transformations are, therefore, also referred to as differentiating processes. 

FIGURE 9.6 A skeletal diversity approach in small molecules library synthesis. 

Kwon, O., Park, S. B., Schreiber, S. L. Skeletal diversity via a branched pathway efficient synthesis of 29,400 discrete, polycyclic compounds and their arraying into stock solutions. J. Am. Chem. Soc. 2002,124, 13402-13404. 

Developing synthetic routes that provide skeletal diversity with multiple core scaffolds or backbone structures is an area of particular current interest. Several approaches to generating such multiscaffold libraries have been advanced. In one straightforward strategy, Schultz synthesized a 45 140-member library from multiple heterocyclic scaffolds, each having a set of functional groups in common [39]. The scaffolds were coupled as building blocks, which were then... 

P.A. Clemons, S.L. Schreiber, Relationship of stereochemical and skeletal diversity of small molecules to cellular measurement space, J. 

A variety of ring-fused systems have been prepared by reaction of pentafluoropyridine and various tetrafluoropyridine systems with difunctional nitrogen nucleophiles. For example, tetrahydropyrido[2,3-Z ]pyrazine and imidazopyridine systems can be prepared by reaction of pentafluoropyridine and appropriate tetrafluoropyridine systems with suitable diamines. The [5,6] and [6,6]-ring-fused systems are also useful substrates for further nucleophilic substitution processes and, consequently, act as versatile scaffolds for the construction of a range of functionalized annelated systems (Fig. 8.10). Of course, such scaffolds are of great interest to the life science industries where access to novel heterocyclic skeletal diversity is a major factor driving the discovery of new chemical entities in lead generation. 

Oguri H, Schreiber SL (2005) Skeletal diversity via a folding pathway synthesis of indole alkaloid-like skeletons. Org Lett 7 47-50... 

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