Skeletal Diversity Construction via a Branching Synthetic Strategy.

Abstract

Cyclopropane derivatives Q 0021Skeletal Diversity Construction via a Branching Synthetic Strategy. -A strategy is described which starts from a fluorous-tagged two carbon unit, e.g. (I), and uses divergent, complexity-generating reaction pathways to create maximum skeletal diversity in the final products. A library of 223 small molecules is synthesized, which have 30 distinct molecular frameworks. -(WYATT, E. E.; FERGUS, S.; GALLOWAY, W. R. J. D.; BENDER, A.; FOX, D. J.; PLOWRIGHT, A. T.; JESSIMAN, A. S.; WELCH, M.; SPRING*, D. R.; Chem. Commun. (Cambridge) 2006, 31, 3296-3298; Dep. Chem., Univ. Cambridge, Cambridge CB2 1EW, UK; Eng.) -M. Paetzel 52-067

Strategies for the Diversity-Oriented Synthesis of Macrocycles

“…The B/C/P algorithm has been a pioneering strategy for the generation of biologically-relevant small molecule libraries, which have afforded several bioactive compounds and probes for elucidating biological phenomena. 46,47,56,[48][49][50][51][52][53][54][55] Furthermore, this systematic approach was applied to the synthesis of a collection of biaryl and bis(aryl)metal-containing medium rings. 57,58 44 In the context of macrocycle synthesis, the pair phase is the macrocyclization of a linear precursor.…”

Scaffold Diversity Synthesis with Branching Cascades Strategy

“…This strategy is more challenging because substrates that can be flexibly transformed into distinct molecular scaffolds need careful synthetic design and planning. Moreover, the synthesis of the molecules should remain more or less combinatorial [43,45,46]. A branching pathway based on the chemistry of Michael adducts (7) was developed by Porco (Scheme 27.2) [47].…”

Diversity‐Oriented Synthesis

“…It is the ability of a DOS to incorporate skeletal diversity into a compound collection that is the most challenging facet of this method and of central importance to its success [18,24,42,45]. The efficient generation of multiple molecular scaffolds is regarded as one of the most effective methods of increasing the overall structural diversity of a collection of molecules and has been reported to "increase the odds of addressing a broad range of biological targets" [11] (relative to a single-scaffold library) [12,19,24,46].…”

“…* Spandl and co-workers have recently developed a related tandem metathesis process that allows the generation of complex polycyclic molecular architectures from substituted norbornene derivatives in a highly efficient and atom-economical manner [50]. A branching DOS strategy was also utilized by Wyatt et al for the synthesis of a skeletally diverse small molecule library (Scheme 3) [46]. The fluorous tagged diazoacetate compound 13 was identified as an attractive starting unit for two main reasons: 1) diazoacetate compounds exhibit enormous synthetic versatility, allowing a wide variety of different synthetic transformations to be carried out on the starting material; and 2) polyfluorocarbon tag technology allowed standard solution-phase parallel synthesis methods to be coupled with the benefits of fluorous-based purification protocols [51,52], thus simplifying the isolation of the library compounds.…”