Introduction. The synthesis of focused, chemical libraries provides incentive and inspiration for the discoveryof novel chemical reactions. Scaffold rearrangement is an attractiveapproach for library development due to the rigid structures thatscaffolds can possess and the stereochemical diversity accessiblethrough asymmetric synthetic processes. These attributes havepreviously been exploited in the synthesis of libraries via the Petasisreaction.1 Recently, diversity-oriented synthesis (DOS)2 hasincreasingly emphasized skeletal diversity involving the structuralmanipulation of scaffolds and synthesis of molecules with distinctskeletal framework.3 The allyl-cation rearrangement of dihydropyran 1(Figure 1A) mediated by Sc(OTf)3 to yield the bispyran 2 illustrateshow a rearrangement process may provide access to compounds thatpossess different shape characteristics. Three dimensional analysisof the two compounds using shape similarity and electrostatics wasaccomplished using OpenEye Scientific Software(www.eyesopen.com, OMEGA and ROCS). The shapefingerprint matching process4 (Figure 1B) characterized the ShapeTanimoto Score as 0.43 and the Tanimoto Electrostatics Score5 as<0.20. The overlay of the two compounds illustrates how the shape ofthe two compounds is distinctly different, evidenced by the lowsimilarity scores, and how scaffold rearrangements may be usefuldiversity-generating processes. However, sequences involvingrearrangements or fragmentations are highly underdeveloped andshould continue to receive attention. We seek to develop syntheticsequences for the creation of novel cyclic scaffolds for library development featuring novel stereoselectiveprocesses. Our approach involves methodologies such as skeletal rearrangements, photochemical-mediatedelectrocyclic processes, cycloaddition reactions, and ring annulations as routes towards accessing skeletaldiversity. In particular, photochemical reactions are highly underdeveloped in diversity oriented synthesis andare very promising for the generation of complex ring systems.An important aspect of functional diversity in the construction of libraries, in which the quality of diversity isoptimal for any given scaffold, is the ability to vary the relative position of diversity elements. Mindful of thisdesign criterion, the topology of target molecules will also be varied by the preparation of structures andscaffolds through efficient and stereoselective rearrangement processes. This approach will optimally displayfunctionality as positional diversity elements. Moreover, the reagents and building blocks employed in thesynthesis of library members will be custom building materials available from other methodologies available tothe CMLD-BU through the various research groups in order to access the greatest chemical diversity availablefrom the Center's resources. In is anticipated that the combination of novel structural rearrangement processesand the use of novel reagents will result in the construction of library compounds rich in chemical functionality,shape diversity, and topologically unique frameworks. Ultimately, the synergistic efforts of the participatingresearchers of the CMLD-BU will enhance the level of molecular complexity accessible in library construction.
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