Molecular diversity by design

1,2,4‐Trisubstituted Cyclopentanes as Platforms for Diversity

“…In a recent publication, Nelson and coworkers [26] and Schreiber [27] illustrated the power of the olefin metathesis reaction for creating diversified libraries containing macrocycles and hence a variety of different molecular frameworks. A core molecular framework in their study was a disubstituted cyclopentene, and a critical feature of their approach was the ability to use a relatively small number of reactions and steps to create high framework diversity.…”

“…All reactions were performed under an inert atmosphere of nitrogen unless otherwise noted. Mass spectrometric analyses were performed by the mass spectrometry facilities at the Purdue University Department of Medicinal Chemistry and Molecular (1b,3b,4a)-4-(Tert-Butoxycarbonylamino)cyclopentane-1,3-dimethanesulfonate (27) Mesyl chloride (0.128 mL, 1.658 mmol) was added dropwise to an ice-cold solution of 26 (120.0 mg, 0.553 mmol) in dry pyridine (2 mL) and the mixture was stirred for 3 h at room temperature under a nitrogen atmosphere. Ethyl acetate was added and the organic layer was washed with water and brine.…”

“…To increase library diversity it is necessary to develop efficient routes to other 1,2,4 (1,3,4)-amino-and hydroxy-substituted cyclopentanes. Although the 32 structures that make up this set (referred to in this manuscript as the 1,2,4-trisubstituted AHCP set) are simple molecules with molecular masses in the range of 115-118, most (27) have never been described in the chemical literature. Schneller and co-workers [10] have reported the synthesis of 4-aminocyclopentane-1,2-diol 6, which was used as a deoxyribose mimic as part of a carbocyclic nucleotide analog.…”

Diversity-oriented synthesis of macrocyclic peptidomimetics

“…Because the overall shape adopted by a given molecule is intrinsically linked to its structure, the overall functional diversity of a smallmolecule library can be correlated (to some extent) with its overall structural diversity (which in turn is proportional to the amount of chemical space the library occupies) (6,8,9,11). In the context of biological screening, the "ideal" library is one of such high structural (and thus functional) diversity that, for any aspect of any biological process, there exists a library compound that is able to modulate that aspect (8,9,15). Although the term "diversity" is somewhat subjective, there are four principle components of structural diversity that have been consistently identified in the literature (8, 9):…”

“…In principle, the screening of such libraries should provide hits against a broad range of biological targets with increased frequency and decreased cost (9). This includes so-called "unduggable" targets and processes that have traditionally been seen as difficult or even impossible to modulate with small molecules (15). Indeed, molecules capable of modulating proteinprotein interactions (29)(30)(31), transcription factor activity (32,33), and multidrug resistance in pathogens (34,35) have all been discovered using DOS libraries, whereas the typical compound libraries employed by pharmaceutical companies or commercial vendors have been largely unsuccessful in providing hits against such challenging and underexploited targets (9,36,37).…”